WO2025076142A1 - Biodegradable implant including naltrexone - Google Patents

Abstract

A subcutaneous biodegradable medical implant is disclosed utilizing naltrexone microspheres with magnesium stearate and polylactide-coglycolide, wherein the subcutaneous biodegradable medical implant is capable of releasing a dosage amount of the naltrexone from the implant following subcutaneous placement of the implant in vivo without causing undesirable reactions at the implantation site.

Description

Atty Ref.: BIOC_001_US BIODEGRADABLE IMPLANT INCLUDING NALTREXONE STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with United States Government financial support under Grant No. 4-UH3- DA-047925-03 awarded by the National Institutes of Health. The United States Government may have certain rights in this invention. BACKGROUND OF THE INVENTION [0001] Naltrexone is a prescription drug belonging to a class of drugs called opioid antagonists. Naltrexone, however, may cause undesirable localized reactions at the site of implantation. Applicant has developed a formulation of naltrexone that ameliorates or otherwise eliminates such reactions, various solutions to which are described with respect to several embodiments described herein. BRIEF SUMMARY OF THE INVENTION [0002] In one aspect, the disclosure provides a subcutaneous biodegradable medical implant comprising relatively pure naltrexone, wherein the subcutaneous biodegradable medical implant is capable of releasing a dosage amount of the naltrexone from the subcutaneous biodegradable medical implant following subcutaneous placement of the subcutaneous biodegradable medical implant in vivo without causing undesirable reactions at the implantation site observed when prior art naltrexone implants are used. The subcutaneous biodegradable medical implant is useful in preventing and treating diseases and disorders in a patient, including addictive disorders (e.g., including opioid use diorder, alcohol use disorder, opioid addiction, alcohol addiction, addictive personality disorders, gaming or gambling addictions, social media addiction, screen addiction, and the like), obesity, and weight gain. [0003] The details of one or more embodiments of the subject matter described in this specification are set forth in the accompanying drawings and the description below. Other features, aspects, and advantages of the subject matter will become apparent from the description, the drawings, and the claims. Atty Ref.: BIOC_001_US BRIEF DESCRIPTION OF THE DRAWINGS [0004] Having thus described the disclosure in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and wherein: [0005] FIG. 1 is a graph plotting the release of naltrexone from BICX in 10 µM phosphate buffer at different pHs over 72 hours. [0006] FIG. 2 is a graph plotting the release of triamcinolone acetonide (TCA) from BICX in 10 µM phosphate buffer at different pHs over 72 hours. [0007] FIG. 3 is a graph plotting the release of naltrexone from BICX in 10 µM phosphate buffer at different pHs over 72 hours. [0008] FIG. 4 is a graph plotting the release of triamcinolone acetonide (TCA) from BICX in 10 µM phosphate buffer at different pHs over 72 hours. [0009] FIG. 5 is a graph plotting the release of naltrexone from BICX in 10 µM phosphate buffer/ 20% EtOH at different pHs over 72 hours. [0010] FIG. 6 is a graph plotting the release of triamcinolone acetonide (TCA) from BICX in 10 µM phosphate buffer/ 20% EtOH at different pHs over 72 hours. [0011] FIG. 7 is a graph plotting the release of naltrexone from BICX in 10 µM phosphate buffer/ 20% EtOH over 72 hours. [0012] FIG. 8 is a graph plotting the release of triamcinolone acetonide (TCA) from BICX in 10 µM phosphate buffer/ 20% EtOH over 84 hours. [0013] FIG. 9 is a process flow chart detailing the variables tested in the order of testing during the development of BICX over 84 hours. [0014] FIG. 10 is a diagram of an exemplary subcutaneous implant placed in a patient according to embodiments of the present disclosure. [0015] FIG. 11 illustrates the insertion procedure and placement of one or two pellets. [0016] FIG. 12 is a graph plotting the data set forth in Table 25 of the mean serum concentration in nanograms per milliliter (ng/ml) against time. [0017] FIG. 13 is a graph plotting the data set forth in Table 30 of the mean serum concentration in nanograms per milliliter (ng/ml) against time. [0018] FIG. 14 plots the Cmax values for Vivitrol® measured against time as reported in Table 31. Atty Ref.: BIOC_001_US [0019] FIG. 15 reports the data generated from a Prodexterone®/BICX-102 single implant tested for 2 months in a rat model and 3 months in a dog model following a subcutaneous route of treatment. The rat data is represented by a circle (●), whereas the dog data is represented by a square (■). [0020] FIG. 16 graphs naltrexone blood levels in ng/ml through time for 6 patients treated with the Wedgewood® implant (1.4g implant compressed at 25 kp). [0021] FIG. 17 graphs the concentration of naltrexone in the plasma of patient after implantation of Prodetoxon®. [0022] FIG. 18 plots the plasma concentration in humans of Vivitrol® over a 24 hour eriod of time. [0023] FIG. 19 are graphs in ng/ml over 30 days for plasma concentration over time curve (bottom) and urine concentration over time (top) for Subject J after implantation of the naltrexone bead for naltrexone represented by an open circle (○) and naltrexol represented by an open triangle ( ^). DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS [0024] Various embodiments of the present disclosure now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the disclosure are shown. Indeed, the disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. The term “or” is used herein in both the alternative and conjunctive sense, unless otherwise indicated. The terms “illustrative” and “exemplary” are used to be examples with no indication of quality level. Like numbers refer to like elements throughout. Within the framework of the present description and in the subsequent claims, except where otherwise indicated, all numbers expressing amounts, quantities, percentages, and so forth, are to be understood as being preceded in all instances by the term “about”. As used herein, the term “about” is defined as ±5%. Also, all ranges of numerical entities include all the possible combinations of the maximum and minimum numerical values and all the possible intermediate ranges therein, in addition to those specifically indicated hereafter. The term "and/or" as used herein is defined as the possibility of having one or the other or both. For example, "A and/or B" provides for the scenarios of having just A or just B or a combination Atty Ref.: BIOC_001_US of A and B. If the claim reads A and/or B and/or C, the composition may include A alone, B alone, C alone, A and B but not C, B and C but not A, A and C but not B or all three A, B and C as components. Definitions [0025] The term "biodegradable," as used herein, refers, in one embodiment, to a material that is degraded in a biological environment. In another embodiment, "biodegradable" refers to a material that has a finite half-life in a biological environment. In another embodiment, "biodegradable" refers to a material that has a measurable half-life in a biological environment. In another embodiment, "biodegradable" refers to a material that is degraded inside a living organism. In another embodiment, "biodegradable" refers to a material that has a finite half-life inside a living organism. In another embodiment, "biodegradable" refers to a material that has a measurable half-life inside a living organism. [0026] The terms "implant" or "implants," as used herein, refers to something implanted into a tissue of a human, in particular pharmaceutically-acceptable, i.e., that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use, controlled/sustained drug delivery systems. The terms also refer to implantable pellet(s). The term “formulation,” more precisely a “pharmaceutical formulation,” as used herein, refers to, in pharmaceutics, is the combination of different chemical substances, including the active drug, in a final medicinal product. [0027] The term "NOAEL," as used herein, refers to "no observed adverse event level." [0028] The term "relatively pure" refers to an implant comprised of 95%, preferably 97.5% or more naltrexone. [0029] In one embodiment, the half-life is 1 month or less. In another embodiment, the half- life is 2 months or less. In another embodiment, the half-life is 3 months or less. In another embodiment, the half-life is 4 months or less. In another embodiment, the half-life is 5 months or less. In another embodiment, the half-life is 6 months or less. In another embodiment, the half-life is 8 months or less. In another embodiment, the half-life is 10 months or less. In another embodiment, the half-life is one year or less. In another embodiment, the half-life is 1.5 years or less. In another embodiment, the half-life is 2 years or less. In another embodiment, the half-life Atty Ref.: BIOC_001_US is 3 years or less. In another embodiment, the half-life is 4 years or less. In another embodiment, the half-life is 5 years or less. In another embodiment, the half-life is 7 years or less. In another embodiment, the half-life is 10 years or less. Each possibility represents a separate embodiment of the present disclosure. [0030] Compositions or methods “comprising” or “including” one or more recited elements may include other elements not specifically recited. [0031] Designation of a range of values includes all integers within or defining the range, and all subranges defined by integers within the range. [0032] Unless otherwise apparent from the context, the term “about” encompasses insubstantial variations, such as values within a standard margin of error of measurement (e.g., SEM) of a stated value. [0033] The singular forms of the articles “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. A. Overview [0034] Various embodiments of the disclosure generally relate to a subcutaneous biodegradable medical implant comprising relatively pure naltrexone (e.g., naltrexone hydrochloride, naltrexone base, naltrexone anhydrous base) that, when implanted in a patient, aids in treatment of diseases and disorders in the patient. In some embodiments, the medical implant further comprises less than 10% cholesterol, preferably about 2%, in the blend and/or as an outer coating. Implants of the disclosure are useful in treating an addiction disorder, including but not limited to opioid use disorder, opioid addition, alcohol use disorder, use of illicit drugs such as, but not limited to, cocaine, methamphetamine and cannabis gambling addiction, gaming addiction, sex addiction, screen addiction, social media addiction, or obsessive-compulsive disorder, particularly in situations when current treatments abate or become ineffective and the cravings or desires return in the treated patient. Implants of the disclosure are useful in treating obesity, weight gain, and weight gain associated with hypothyroidism, Hashimoto's thyroiditis, polycystic ovary syndrome (PCOS), or sleep apnea. Implants of the disclosure are useful in treating chronic pain, inflammation, and complex regional pain syndrome in the patient. [0035] The molecular formula for naltrexone is (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)- 4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Atty Ref.: BIOC_001_US (C₂₀H₂₃NO₄). It will be appreciated that naltrexone may also be referred to as Vivitrex, ReVia, N-cyclopropylmethylnoroxymorphone, Vivitrol®, Celupan, Naltrexonum, Trexan, Naltrexona, Naltrel, N-Cyclopropylmethyl-14-hydroxidihydromorphinone, among others. The present application applies to the use of the identified molecular formula, regardless of what terminology is used to reference it. [0036] It will be appreciated that the biodegradable embodiments of the present disclosure eliminate a need for physical or intentional removal of the implants from a patient. The implant comprising naltrexone may biodegrade into the bloodstream, eliminating the requirement for removal of the implant, over a varying number of days or months depending on the metabolism of the patient. The implant comprising naltrexone provides a sustained release of naltrexone into the bloodstream of the patient. The implant comprising naltrexone provides a gradually descending sustained level of release of naltrexone into the bloodstream of the patient over the course of treatment. Such sustained release of naltrexone into the bloodstream overcomes several drawbacks associated with oral-based medication administration systems. [0037] The present implants comprising naltrexone eliminate the need for oral administration, which eliminates the need for a patient’s liver to process the drug. Such a bypass is significantly beneficial for those patients with fatty liver disease and other conditions that would prohibit a patient from processing naltrexone in a healthy manner. An implant opens the door for patients who may not otherwise be candidates for treatments involving administration of naltrexone. Additionally, oral administration tends to require a higher dosage than is required when using an implant. [0038] Further, in an oral-based naltrexone administration system, non-compliance with the medication plan is a common issue. Reasons for non-compliance include a patient forgetting to take the medication at the scheduled time (e.g., forgetting to take the medication every day; forgetting to take the medication at the same time each day) and a patient opting not to take the medication as a result of distaste for or discomfort related to possible side effects, for example gastrointestinal complaints, including but not limited to, diarrhea and abdominal cramping, liver damage, and more. Examples of side effects associated with oral administration of naltrexone may include symptoms of anxiety, allergic dermatitis, arthralgias, myalgias, insomnia, fatigue, skin rash, headache disorder, nausea, vomiting, abdominal pain with cramps, angioedema, Atty Ref.: BIOC_001_US among others. Such non-compliance significantly reduces likelihood of long-term success of a treatment regimen. [0039] Patients receiving administration of naltrexone sometimes preferably meet certain physical requirements in order for the implant to be safe and successful. Examples of such physical requirements vary according to the intended treatment or indication, and may include without limitation specific liver enzyme levels, certain BMI levels, and the patient should not be taking any opioids. [0040] Adverse reactions at the implantation site have been reported (Krupitsky E et al. (2012), Arch Gen Psychiatry, 69(9):973-81). These reactions include, but are not limited to, swelling, redness, pain and itching. Applicant has discovered that an ingredient found in many naltrexone formulations (See, U.S. Patent 6,203,813 (Gooberman, 2001)), triamcinolone acetonide (TCA), believed to prevent adverse tissue reactions, is actually the cause of such adverse tissue reactions. In addition, Applicant has found that a common carrier used in prior art formulations, magnesium stearate, when used in excess amounts, can also contribute to the adverse tissue reactions observed in many patients receiving such implants. Russian Patent No. 2620254 (Saksena K et al., 2017) teaches "that magnesium salts or magnesium stearate in combination with naltrexone in implantable tablets cause irritation and inflammation at the site of implantation.” Applicant found, however, that magnesium stearate in amounts less than 1.5%, preferably less than 1.2%, more preferably about 1.08%, of the total mass of formulation is the minimum amount of magnesium stearate required to prevent “sticking” during the formation of the implant while not causing adverse reactions at the implant site. “Sticking” during the manufacturing process results in uneven and/or inconsistent implants and the inability to use a fully automated, hydraulic pellet press to produce uniform and/or consistent implants Applicant, however, discovered that use of magnesium stearate in amounts greater than 1.2% of the formulation resulted in the site implantation irritation as reported in the art (Ibid, Krupitsky E et al.) Finally, Applicant discovered that use of poly-lactic acid-based polymer matrixes, such as poly(lactic-co-glycolic acid), (“PLGA”) to coat an inner naltrexone core as described in Russian Patent No. 2620254 (Ibid, Saksena K et al.) and U.S. Patent No. 7,914,802 (O’Neil, 2016) was undesirable as such polymers take longer to be bio-absorbed than the naltrexone core giving false impressions that the implant still contains naltrexone. In addition, un-absorbed poly-lactic acid based polymer matrixes can result in the undesirable appearance of lumps. Applicant has Atty Ref.: BIOC_001_US developed a formulation that does not include triamcinolone acetonide (TCA) and poly-lactic acid-based polymer matrixes, and includes only trace amounts of magnesium stearate, to minimize, reduce or eliminate adverse site reactions found in the prior art implants while providing enough magnesium stearate to prevent sticking and allow for adequate compression using a commercially automated pellet press. The present invention is directed to implants containing 97.5% or more naltrexone that are capable of being manufactured on semi- or fully- automatic pellet press due to the inclusion of a small percentage of magnesium stearate. The preferred embodiment does not contain triamcinolone acetonide (TCA). B. Composition of Naltrexone Pellets and Process to Manufacture [0041] In some embodiments, the subcutaneous biodegradable medical implant may comprise other excipients and/or non-active ingredients as part of the manufacturing process. Exemplary excipients and/or non-active ingredients may include cholesterol. [0042] One embodiment of the present invention is directed to a robust process to produce reproducible implantable pellets containing naltrexone (NTX) at scale. To confirm the dissolution rate in vitro and release rate of the naltrexone in vivo in a pig model of the pellets, placebo pellets were manufactured. The pellets were manufactured and tested by IRISYS, Inc., San Diego, California (US). [0043] The compositions of the placebo and the naltrexone-based pellets are provided in Tables 1a – 1c Table 1a: Composition of placebo Naltrexone pellet (implant) Item # Ingredient^{Amount per} Function I_{m lant (m )} se e

Atty Ref.: BIOC_001_US Magnesium Stearate, Hyqual^® Lubricant (Mallinckrodt, Inc., St. Louis, M V t l NF

Table 1b: Composition of Naltrexone alone pellet (implant) Item # Ingredient^{Amount per} Function I_{mplant (mg)} Tab

e c: Compos on o combna on a rexone/ramcnoone aceonde ( C ) pe et (implant) Item # Ingredient^{Amount per} Function I_{mplant (mg)} e nd le

Atty Ref.: BIOC_001_US B1. Materials and Equipment [0044] Details of the materials used are listed in Tables 2a - 2b Table 2A: List of materials Material Manufacturer Lot # N_{altrexone base}^{Noramco®, Inc., Wilmington,}_{6064730 6066328}

q p V-blender BL-001 (Munson® Machinery Co., Inc., Utica, NY)

[0045] The process involved material de-lumping, triamcinolone acetonide (TCA) and magnesium stearate blending with naltrexone, pellet compression, packaging, and gamma - sterilization. The first blend was prepared based on the provided procedure. In one embodiment, 100g of naltrexone (NTX) sample, 1g of TCA sample and 1.1g of magnesium stearate sample were passed through 18-mesh screen and blended into a plastic bag. Other embodiments did not contain TCA, only naltrexone and 1.1g of magnesium stearate. The resulting blend was passed through an 18-mesh screen three (3) times to de-lump and to ensure uniformity. Pellets were compressed on a Natoli® NP20A single punch hydraulic pellet press (Natoli® Engineering Company, Inc., Saint Charles, MO) using an 8.4mm round flat face tooling. The pellet press was run in manual mode and the die was filled with a pre-weighed amount of the blend (1.021g). The press did not have a double fill/pre-compression option in manual mode, so the blend was manually pre-compressed between two plastic sheets to simulate dry granulation or roller Atty Ref.: BIOC_001_US compaction and then the die was filled with the blend. An 8.4 mm round flat face tooling (Table 3) was used during the compressing step. Table 3: Compression of blend R-0954-01 to produce pellet R-0954-01-03 and R-0954-01-05. Pellet blend Thickness Compression pressure, Pellet description number set point, kN .

B3. Dissolution Method Development [0046] Acceptable pellets from the blend were used for in vitro dissolution method development; an important tool used for development and approval of generic dosage forms. The pellets were tested using different media at different pHs as shown in Table 5 in Stage 1 of dissolution method development. The parameters used in the dissolution study are given below. B3.1 Stage 1. Dissolution Method Parameters Determined [0047] A USP dissolution apparatus II (paddle) (Agilent Technologies, Inc., Santa Clara, CA) was used for dissolution method parameters selection. For accelerated dissolution method development multiple parameters were evaluated: 1). temperature of the dissolution media; 2). initial wetting of the pellet (by adding detergent and organic solvent); 3). the mixing speed; and 4). the pH of the dissolution media used. [0048] Water was used as the starting media. A sampling timepoint (at 66 or 90 hours) was used for initial dissolution parameter assessment.

Atty Ref.: BIOC_001_US Table 4. Results of the initial assessment of influence of different dissolution parameters (n=1) 20% 20mM 0.1% 10mM Dissolution EtOH, 0.05N Acetate Water SLS in PBS H H

1. a higher temperature increased dissolution rate of the naltrexone slightly; 2. a lower pH increased the dissolution rate of the naltrexone; 3. the addition of 20% ethanol (EtOH) in water almost doubled the dissolution rate of the naltrexone compared to water alone, however, 100% of release was not achieved over 90 hours. It is expected that increasing the percentage of EtOH will not positively impact dissolution rate since solubility of naltrexone hydrochloride in EtOH is low (<1mg/mL) and doubling of the dissolution rate is explained with EtOH helping to “wet” the pellet; 4. the addition of 0.1% SLS did not significantly improve dissolution rate; 5. 100% dissolution of naltrexone was achieved over 66hrs in a 0.05N HCl and 20mM acetate buffer of pH 3.8; and 6. a phosphate buffered saline (PBS) buffer of a pH 7.4 provided higher dissolution rate than water. B3.2 Stage 2. Dissolution Method and Parameters Optimization [0050] As 100% dissolution was achieved at pH 1 and pH 3.8, and pH 7.4 provided only 42.51% dissolution as per the data from Stage 1 dissolution method development, for Stage 2 of development two types of physiologically relevant buffers were screened: Atty Ref.: BIOC_001_US phosphate buffer and acetate buffers at 10mM concentration in a range of pH 3.8 to 7.4 with more rigorous sampling. The results are shown in Tables 5 through 8 and FIGs. 1-4. Table 5. Release of naltrexone from pellets in 10mM phosphate buffer at different pHs (n=1) 10mM phosphate buffer 10mM phosphate buffer 10mM phosphate buffer pH Time, pH pH 7.4150RPM at 37⁰C h

Table 6. Release of triamcinolone acetonide (TCA) from pellets in 10µM phosphate buffer at different pH (n=1) 10mM phosphate 10mM phosphate 10mM phosphate buffer pH Time, buffer pH 5.050 RPM buffer pH 6.050 7⁰ hrs .4150 RPM at 37 C

Time, 10 mM Acetate buffer 10 mM Acetate buffer pH 10 mM Acetate buffer h H 3850 RPM at 37⁰C 5050 RPM at 37⁰C H 5850 RPM at

different pH (n=1) Time, 10 mM Acetate buffer 10 mM Acetate buffer pH 10 mM Acetate buffer hrs H 3850 RPM at 37⁰C 5050 RPM at 37⁰C H 5850 RPM at

Atty Ref.: BIOC_001_US [0051] As evidenced in FIGs. 1 and 3, the dissolution of naltrexone is pH-dependent and a desirable dissolution profile is achieved by modifying the pH of the dissolution media. As observed in the Stage 1 dissolution method, a lower pH yielded a higher dissolution of naltrexone. A similar trend was observed in both the phosphate and acetate buffers. The dissolution profile was comparable in 10 mM at pH 5.0 phosphate buffer to the same pH 10 mM acetate buffer. Since the phosphate buffer was more physiologically relevant; it was therefore, selected for future experiments. Medias with a pH of 5.0 or lower, dispersed the pellet after 72 hours and none of the conditions provided a 100% release of triamcinolone acetonide (TCA) due to its lipophilic nature. As we 100% TCA release was not achieved, as illustrated by FIGs. 2 and 4, Stage 3 focused on further improving the yield of TCA. B3.3 Stage 3. Dissolution Method and Parameters Optimization [0052] The dissolution tests were performed in “sink” conditions where the amount of solvent was at least 3 times higher than the minimum amount of solvent required for dissolution. The saturation solubilities of naltrexone in different media are listed in Table 9. Table 9: The saturation solubility of Naltrexone in different media Solubility in

Atty Ref.: BIOC_001_US [0053] The solubility of triamcinolone acetonide (TCA) in water is approximately 20 mg/L. The salting-out effect of phosphate and acetate buffer can decrease the solubility of triamcinolone acetonide (TCA). Therefore, for the next step of the dissolution method development, 20% of ethanol was added to the dissolution media with a phosphate buffer. The following dissolution media were evaluated: ^ 10 mM phosphate buffer / 20% EtOH pH 6.0 ^ 10 mM phosphate buffer / 20% EtOH pH 6.5 ^ 10 mM phosphate buffer / 20% EtOH pH 7.0 Results of the dissolution testing are reported in Tables 10 and 11 and FIGs.5 and 6. Table 10. Release of naltrexone from pellets in 10 mM phosphate buffer / 20% EtOH at different pH (n=1) pH 6.0 pH 6.5 pH 7.0 Time, hrs 50/75RPM* at 37⁰C 50/75RPM* at 37⁰C 50/75RPM* at 37⁰C N d

Table 11. Release of triamcinolone acetonide (TCA) from pellets in 10mM phosphate buffer / 20% EtOH at different pH pH 6.0 0 pH 6.5 pH 7.4 Time, hrs 50/75 RPM* at 37 C 50/75 RPM* at 37⁰C 50/75 RPM* at 37⁰C N

ote: speed was accidently increased from 50 RPM to 75 RPM at the 8 hour time point during the autosampler setup. B3.4 Stage 4. Dissolution Method and Parameters Optimization [0054] Dissolution parameters: PBS buffer with 20% Ethanol at pH 7.0, 50 RPM mixing, and 37⁰ C. ^ naltrexone lot #1 (length 16±0.25 mm, diameter 8.4 mm, compression pressure 5±0.5 kN, direct compression without precompression) (n=1); and ^ naltrexone lot #2 (length 6 mm (side) or 8.68 mm from top to bottom, diameter 12 mm, compression pressure is 13.5±0.5 kN, direct compression without precompression) (n=1). Atty Ref.: BIOC_001_US Samples were taken at 8, 24, 48, 72 and 84 hours. [0055] Results of the dissolution testing are reported in Tables 12 and 13 and FIGs.7 and 8. Table 12. Release of naltrexone from pellets in 10mM phosphate buffer / 20% EtOH Lot #1 Lot #2 Time, hrs Table 13. Release o

EtOH at different pH. Naltrexone lot #1 Naltrexone lot #2 Time, h B4.Process

[0056] The overall goal of the development of naltrexone (NTX) implantable pellets was to identify a process that will yield uniformly hard pellets without using excessive compression force. As NTX pellets will be used subcutaneously for long-acting indication, developing a pellet with significant hardness is desirable as hardness and dissolution are inversely related. For the development, the target hardness was 30kg. The main process steps and variables identified during the development work are illustrated in FIG. 9. [0057] During the compression, the following problems were observed: ^ Ejection of the pellets. The pellet press was not able to eject compressed pellet; and ^ Over-compressed pellets have tendency to laminate. [0058] Dissolution was performed for the lots of pellets. It was shown that the following parameters affect release of naltrexone: ^ Pellet shape: Pellets with lower surface area dissolved longer than pellets with bigger surface area; Atty Ref.: BIOC_001_US ^ Amount of magnesium stearate: magnesium stearate is a hydrophobic material, increased amount of magnesium stearate significantly decreases in-vitro release of the active ingredients; ^ Compression pressure: harder the pellet, slower the in-vitro release of the active ingredients, but if pellet is over compressed, hardness of the pellet drops significantly; and ^ Lubrication of the die helps with pellet ejection and allows for a greater compression resulting in denser pellets. [0059] For blend R-0954-01-032, the process used for blend R-0954-01-016 was repeated with the exception of the use of a smaller screen mesh-200 instead of a mesh-30. The observed total blend size was 300g. [0060] Two different lots of pellets (R-0954-01-33 and R-0954-01-34 1.5g pellet) were compressed out of this blend as horizontal or oblong shaped pellets. The thickness ranged from 2.75 -4.5 mm and the compression force ranged from 30.3 kN for 2.75mm thick pellets to 9.92 kN for 4.5 mm thick pellet. At the higher compression forces, lamination was observed. Lot 34 consisted of oblong pellets with an average weight of 1.5g. The thickness of these pellets ranged from 4.9 mm to 6.5 mm. The pellets laminated at higher compression forces. The final settings were a thickness of 6.5 mm and force of 16 ± 2.5 kN. More NTX based pellets were produced, i.e., lots R-0954-01-39, R- 0954-01-40, R-0954-01-41, that were all oblong in shape, based on R-095401-16 using the blends R- 0954-01-38 and R-0954-01-46. The pellets of lot R-0954-01-39 were 8mm thick with a of 10.0mm. Pellets with higher compression resulted in pellet having a lower thickness which resulted in lamination. The pellets of lot R-0954-01-40 were 3 mm in thickness and pellets of lot R-0954-01-41 were 5.75 mm thick. [0061] The process used to prepare blend R-0954-01-46 was similar to the process used to blend R-0954-01-38. Both blends R-0954-01-49 and R-0954-01-50 (1.5g) were compressed from blend R-0954-01-46. The resulting pellets were oblong. [0062] For blend R-0954-01-49, pellets with thicknesses ranging from 2.75mm – 4.0 mm were tested with compression forces ranging from 24.9 kN to 11.9 kN. For lot R-0954-01-50, pellets of 1.5 g were compressed with thicknesses ranging from 3.25 - 4.0 mm. It was observed that pellets with lesser thicknesses, increased compression forces. It was observed that pellets laminated at 3.0 and 3.25 mm thicknesses. Approximately 30 pellets were prepared having 3.5 mm thicknesses. [0063] Lamination and/or pellet ejection problems were observed for all the blends produced. It was theorized that there is no optimum lubrication. To test this theory, batches of the blends were prepared with differing levels of lubrication. For example, a significant quantity of magnesium stearate (MgS) was initially added with an amount of triamcinolone acetonide (TCA) either before and/or after the selected Atty Ref.: BIOC_001_US granulation process, i.e., intra-granular and extra-granular MgS. For blend R-0954-01-55, the wall of the blender was also coated with MgS by adding excess MgS and running the blender. It was discovered, however, that pre-coating the walls of the blender did not offer adequate control of the lubrication. [0064] The properties of a blend were driven by the different blend sizes. Magnesium stearate (MgS) is critical in determining the physical properties as well the release of naltrexone (NTX) and is required to be controlled systematically. The summaries of processes in the next phase of development are summarized in Table 14. Table 14: Summary of manufacturing process for different blends for NTX based pellets 0954-01-51 (NTX alone) R-0954-01-53

Atty Ref.: BIOC_001_US Return to V blender. Add Add 50% NTX to the V blender 50% NTX to the V blender [

the results are reported in Tables 15-17. Table 15: Summary of manufacturing process for different blends for NTX based pellets R-0954-01-57 (BICX-102) R-0954-01-60 and R-0954-01-65 0 2⁰ h

Atty Ref.: BIOC_001_US Add mixture to the blender and remaining NTX and blend for 20 minutes Table 16: Summary of manufacturing process fo

R-0954-01-71 and R-0954-01-76 n

Atty Ref.: BIOC_001_US Add granulated blend to V blender and add 20% MgS (extra granular) T

R-0954-01-68 (Placebo implant) Weigh and transfer spray dried lactose and cholesterol to the robot coupe h

[0066] Blend 0954-01-51 was manufactured without the addition of triamcinolone acetonide (TCA), as pellets comprised of naltrexone (NTX) without any additional ingredients would be likely candidates for clinical trials. The manufacturing steps for producing blend 0954-01-51 were similar to the steps to produce blend R-0954-01-16, except in the 1^st step, only magnesium stearate (MgS) was used. Pellets made from blend R-0954-01-55 were prepared by using blend R-0954-01-051. A 10 mm flat face tooling instrument was used during the compression step. Final settings for these pellets are listed in Table 18.

Atty Ref.: BIOC_001_US Table 18: Compression parameters for pellets (R-0954-01-55) Force set point 16 kN Thickness 9.75mm [

sterilization by gamma-irradiation. [0068] Blend R-0954-01-053 was prepared containing naltrexone (NTX) and triamcinolone acetonide (TCA) using the same procedures for blends R-0954-01-38 and R-0954-01-46 with a total blend size of 500 g. Blend R-0954-01-57 was prepared using blend R-0954-01-53. [0069] For blend R-0954-01-57 (Table 15), an additional lubrication step was performed where about 20g of magnesium stearate (MgS) was added to the blender and blended for 1 min to coat the walls thereof. MgS was discharged and 100g of blend R-0954-01-53 was added to the blender and the lubrication step was repeated for the rest of the blend. Pellets with compression force of up to 18kN were acceptable, but 21.75 kN were over-compressed. The force set point was 15.3 kN (although it may range from 13.6 kN ±5% to 18.2 kN ±5%, thickness set point was 9.85 mm and the dosing set point was 20.51 mm. About 400 pellets were manufactured, packaged, and sent for sterilization. [0070] For blend R-0954-01-60 that contains a mixture of naltrexone (NTX) and triamcinolone acetonide (TCA), the production process was modified by including the additional steps of adding approximately 20% MgS (intragranular) before roller compaction step and approximately 80% MgS to the granulated blend (extra-granular) after the compaction step. Extra- granular MgS aids in lubrication of the pellet press during manufacturing. The thickness testing varied from 9.25 to 9.65 mm and the compression forces ranging from 13.6 kN – 19.6 kN ±5%. [0071] Approximately, 80% intragranular magnesium stearate (MgS) was added to blend R-0954-01-71 before roller compaction and 20% extra-granular blend. The subsequent steps were similar to the overall manufacturing process where naltrexone (NTX) was addressed in geometric progression and the blend was screened before the addition of NTX. [0072] Batch R-0954-01-76 were manufactured using similar procedures used to manufacture theR-0954-01-71 pellets wherein 80% of the MgS was added intra-granularly and remaining 20% was added post granulation (extra-granular). Differing die dwell times were tested Atty Ref.: BIOC_001_US to optimize the hardness and porosity of the pellets. The pellet press required advanced settings to reduce or eliminate compression force decay while the pellets are being compressed. The inventors consulted with the pellet press manufacturer (Natoli® Engineering Co., Inc., St. Charles, MO) for the advanced settings. Lots R-0954-01-55, R-0954-01-57, R-0954-01-63, R- 0954-01-67, R-0954-01-73 and R-0954-01-74 were tested for use in good laboratory practices (GLP) animal studies. The lead was determined based on the results of the in vivo testing. B5. Container -Closure system [0073] For the clinical development work, pellets were packaged in 5 mL BD Luer-Lok^TM sterile parenteral grade syringes (Becton, Dickinson and Company, Franklin Lakes, NJ). The filled syringes were placed within self-sealing pouches GS Medical Packaging, Inc. (GS Medical Packaging, Inc., Etobicoke, ON, CA). B6. Sterilization [0074] The naltrexone implants were processed in ExCell® precision irradiator (SteriGenics® U.S., Oak Brook, IL) at ambient temperature. The processing chamber is pre-dose mapped for various densities/geometries and the absorbed doses are calculated by placing 2 dosimeters on the outside and applying adjustment factors to the recorded doses. Each run had a 25-40 kGy dose range. B7. Stability Testing [0075] Compatibility with the dosage device: The solid implantable pellet is placed within the sterile syringes. The interaction of the solid pellet with the syringe device was not expected. Stability data for 7 months at room temperature and accelerated conditions (40°C/75%RH) for lots R-0954- 01-55 (NTX alone), lot R-0954-01-67 (NTX/TCA combination) and placebo (TCA alone) are reported in Table 19.

Atty Ref.: BIOC_001_US Table 19: Summary of dissolution testing on different lots Lot Number Blend lot#^P d_e^e s^ll c^e r^t i_ption Medias used (number of pellets) C C C C C C C C C C C C C

Atty Ref.: BIOC_001_US R-0954-01-33 R-0954-01-32 oblong PBS, pH 7.4, 50 RPM, 37°C (3) Hank’s buffer pH 7.450 RPM, 37°C (3) R-0954-01-34 oblong PBS pH 7.4 50 RPM 37°C (3)

C. Therapeutic Uses of Naltrexone Implants and Proof of Concept [0076] Various embodiments of the present disclosure generally relate to a subcutaneous biodegradable medical implant comprising relatively pure naltrexone (e.g., naltrexone hydrochloride, naltrexone base, naltrexone anhydrous base) without triamcinolone acetonide (TCA) and with less than 2% magnesium stearate that, when implanted in a patient, aids in Atty Ref.: BIOC_001_US treatment of a disease or disorder in the patient, such as impulse control and behavioral disorders. Implants of the disclosure are useful in treating addiction disorders, including but not limited to Opioid Use Disorder (OUD), Alcohol Use Disorder (AUD) and opioid and/or alcohol addictions, food addiction, pornography addiction, methamphetamine, gambling addiction, gaming addiction, sex addiction, screen (computer/internet) addiction, work addiction, exercise addiction, spiritual addiction, shopping addiction, harm-to-self addictions (cutting), social media addiction, or obsessive-compulsive disorder. Implants of the disclosure are useful in treating obesity, weight gain, and weight gain associated with hypothyroidism, Hashimoto's thyroiditis, polycystic ovary syndrome (PCOS), or sleep apnea. Implants of the disclosure are useful in treating chronic pain, inflammation, and complex regional pain syndrome. C1. Animal Studies- Preliminary [0077] The potential toxicity of the test articles, BICX-102 and BICX-104, was tested. Both were administered as subcutaneous implants into Yucatan minipigs (BioChemed Services, Winchester, VA) to evaluate the potential reversibility of any findings. In addition, the toxicokinetic (TK) characteristics of BICX-102 and BICX-104 were determined. Naltrexone subcutaneous pellets (implants) BICX-102 is comprised of naltrexone and triamcinolone acetonide (TCA) as the pharmaceutical ingredients. BICX-104 is naltrexone as the pharmaceutical ingredient without triamcinolone acetonide (TCA). Both, BICX-102 and BICX- 104 contain small amounts of magnesium stearate as an excipient, primarily as a lubricant. BICX-102 and BICX-104 are currently under development for the treatment of alcohol and opioid use disorders. The details of the aforementioned in vivo studies are set forth in Table 20. Table 20: Experimental Design^g Necropsy (No. of Animals) N f A i l M i R M i R ry ± 3

Atty Ref.: BIOC_001_US Necropsy (No. of Animals) No. of Animals TA Main Recovery Main Recovery R Im l ntd n TA ± 3

Atty Ref.: BIOC_001_US Necropsy (No. of Animals) No. of Animals TA Main Recovery Main Recovery R Im l nt d n TA ± 3

n ma s were/w e ose on ays , ± , an ± an ma n a ne un ay ± d Side of implantation alternated at each surgical procedure. e Acute Phase animals (4/sex) were submitted for necropsy on Day 14 following implantation for the main acute terminal animals, and 2 animals/ sex for Recovery necropsy were submitted for necropsy on Day 30. f Triamcinolone acetonide (TCA) g This table includes the experimental design for the entire duration of the study; however, this interim report only includes data collected through the Day 182 ± 1 necropsy. [0078] Based upon the results included in this interim report, it was surprisingly discovered that the BICX-104 implant had no observable adverse effect level (NOAEL) in Yucatan minipigs. The establishment of the NOAEL was based on the absence of any systemic effects and upon the non-adversity of the microscopic findings. C2. Study Design [0079] The potential toxicity of BICX-102 and BICX-104, when given as a subcutaneous implant to minipigs was studied. In addition, the potential reversibility of any findings, was evaluated. Also, the toxicokinetic (TK) characteristics of BICX-102 and BICX1-04 were determined. Both are naltrexone subcutaneous implants; BICX-102, with naltrexone and triamcinolone acetonide (TCA) as the pharmaceutical ingredients; and BICX-104, with naltrexone as the pharmaceutical ingredient only. Both also include magnesium stearate as an excipient, for lubricating purposes, and both are currently under development for the treatment of alcohol and/or opioid use disorders. C3. Test Article, Placebo Article, and Inert Article Identification Table 21: Test Article Identification Identification BICX-104 BICX-102 BICX-102 BICX-102 BICX-102 BICX-102 N ltr x n + N ltr x n + TCA s)

Atty Ref.: BIOC_001_US Table 22: Placebo and Inert Article Identification I_{dentification}^{Placebo (11 mg MgS} Placebo (11 mg MgS o_{nly) and 10 mg TCA}^{PTFE Sham implant} Batch (Lot) No. R-0954-01-69 R-0954-01-70 58973

M^{edication Interval, Dose Level, and Route} S_{urgery (Day 1, 91 ± 2, and 182 ± 2)}

b Additional administered as needed. c Administered to 1 Group 5 male (Animal No.5002).1 Group 6 male (Animal No.6006), and 1 Group 2 male (Animal No.2006) during the Day 1 surgery. d Administered as needed to some animals. e Administered to 1 Group 6 male (Animal No.6006) during the Day 1 surgery. f Additional 4 mL was administered to 1 Group 5 female (Animal No.5505) IM – Intramuscular PRN – As needed INF – Infused into incisions LRS – Lactated Ringer’s solution INH – Inhalation IV – Intravenous SC – Subcutaneous C4. Surgical Procedure [0080] Skin incisions were made in the pre-scapular region of the neck/withers (approximately 1.5 cm in length); discrete subcutaneous pockets were created using a 10.5 mm trocar. Skin incisions made in the abdomen were approximately 1.5 cm in length; discrete subcutaneous pockets were created using a 10.5 mm trocar. The corners of an approximately 5 x 4 cm or 5 x 5 cm square were tattooed around the appropriate left or right implant sites (pre-scapular or Atty Ref.: BIOC_001_US abdominal region). The incisions were closed using absorbable suture and the skin closed with tissue glue. Digital photographs were taken. C5. Justification of Route and Dose Levels [0081] Implantation is the intended route of administration of this test article in humans. The dose levels were selected based on information provided by the Inventor indicating that the human clinical dose is 1 to 2 g of naltrexone (NTX), and 10 to 20 mg of triamcinolone acetonide (TCA) and 11 to 22 mg of magnesium stearate (MgS) per subcutaneous implant that is slowly released over 3 months (90 days) which is equivalent to a 11 to 22 mg/kg/day NTX dose and 0.11 to 0.22 mg/kg/day TCA dose. C6. Body Weight and Body Weight Change [0082] Implantation of the test article was not associated with any effects on body weight values over the course of the study. Animals gained weight at approximately the same rate over the 182-day period included in this report. Occasional differences from controls were noted but were of low magnitude and considered to reflect normal biological variation. C7. Skin Reaction [0083] All placebo, PTFE, and test article implantation sites were observed with very slight erythema and very slight edema on at least one occasion. The number of occurrences of erythema and edema were increased in implantation sites that received BICX-102 (regardless of the number of sites or implants per site), but much less so for BICX-104, the formulation that did not contain triamcinolone acetonide (TCA). Scores greater than very slight erythema were noted on occasion and were typically transient in nature resolving by the next observation interval. As the majority of skin reaction scores were very slight (barely perceptible) the increase in occurrence in test- article implanted sites is considered non-adverse due to the low severity. [0084] Group 2 was observed with an increase in the mean score for severity of edema, which was attributable to a single animal (Animal No. 2505) that was receiving veterinary treatment for significant swelling of the implantation site along with other observations that were indicative of a possible infection and was thus not considered test article related. Following a single subcutaneous implant of 1 g NTX (Group 2) and 1 g NTX with 10 mg TCA (Group 3), individual Cmax and AUC values appeared to be similar. Systemic exposure to NTX did not appear to be impacted when administered with TCA. Atty Ref.: BIOC_001_US C8. Implant Sites (up to Day 91±2 necropsy) [0085] Test article-related microscopic findings at the implant site occurred on Day 14±2, 28±2, and 91±2 at all BICX-102 and BICX-104 implant sites compared to PTFE sham implant (Day 14±2 and 28±2) and/or MgS placebo, TCA/MgS placebo or PTFE sham implants (Day 91±2). In general, BICX-102 associated implant sites had greater inflammatory cell infiltrate and localized tissue response (necrosis, hemorrhage, crust, ulceration, bacterial infiltration) compared to BICX-104, and the various placebo or sham controls. MgS and TCA/MgS placebo implants also had greater inflammatory cell infiltrate and localized tissue response when compared to PTFE sham implant. [0086] Adipose tissue at the implant site was evaluated and no overt changes in adipocyte character were noted outside of the inflammatory cell infiltrates and localized tissue responses noted below. C9. Implant Sites (Day 91±2 necropsy) [0087] Test article-related microscopic findings were evaluated for the three test article implant conditions: single BICX-102, double BICX-102 (two BICX-102 implants in a single pocket), and single BICX-104. Test article implants were compared to placebo magnesium stearate (MgS), placebo triamcinolone acetonide (TCA)/magnesium stearate (MgS), sham implant (PTFE), double sham implants (two PTFE implants in a single pocket), and control (normal skin). All implanted sites examined had some amount of leukocyte infiltration and associated findings, though the incidence, composition and density varied. In general, BICX-102 and double BICX- 102 implant sites had greater individual cell and total cell infiltrates than the various placebo groups and a more severe localized tissue response (necrosis, mineralization, fibrosis, etc.). BICX- 104, the TCA and MgS placebo implant sites were roughly equivalent and consistently had greater cellular infiltrate than PTFE. BICX-102 and BICX-104 implant sites also had fibrosis, mineralization, or central cavitation, which were not consistently present in MgS and TCA/MgS placebo implant sites. [0088] BICX-102 and double BICX-102 implants had increased neutrophilic infiltration, increased necrosis, increased overall cell parameters, increased mineralization, increased fibrosis, the presence of cavitation with an eosinophilic core, increased erosion/crust/ulceration, increased thrombi in small vessels, occasional squamous metaplasia of the implant pocket, bacterial infiltration, and increased hemorrhage compared to placebos (MgS and TCA/MgS) and PTFE. Atty Ref.: BIOC_001_US When compared to BICX-104; BICX-102 and double BICX-102 implant sites had increased neutrophils, lymphocytes, necrosis, and overall total cells with decreased giant cells, increased non-cellular parameters included erosion/crust/ulceration, thrombi, metaplasia, and bacterial infiltration. Table 24: BICX-102/BICX-104 Comparison Day 91±2 Males 4

ep ese e as u e p ese . The scale for necrosis was 0-4. (1= minimal, 2= mild, 3=moderate and 4=severe)

Atty Ref.: BIOC_001_US Table 25: BICX-102/BICX-104 Comparison Day 91±2 Females BICX 102 4

C10. Implant Sites (up to Day 182±2 necropsy) [0089] Test article-related microscopic findings were evaluated for the three test article implant conditions: Single BICX-102, double BICX-102 (two BICX-102 implants in a single pocket), and single BICX-104. Test article implants were compared to placebo magnesium stearate (MgS), placebo MgS with triamcinolone acetonide (TCA), sham implant (PTFE), double sham implants (two PTFE implants in a single pocket), and control (normal skin). All implanted sites examined had some amount of leukocyte infiltration and associated findings, though the incidence, composition and density varied. BICX-104 evaluation was limited to a single implant site/sex/group which limited interpretation of this test condition at this time point. In general, BICX-102 and BICX-104 associated implant sites had comparable localized tissue response in males and increased inflammatory cell infiltrates and localized tissue response in females compared to placebo and sham controls. Atty Ref.: BIOC_001_US [0090] Adipose tissue at the implant site was evaluated and no overt changes in adipocyte character were noted outside of the inflammatory cell infiltrates and localized tissue responses noted below. [0091] In males, BICX-102 and double BICX-102 implants generally had similar or decreased total cell infiltrates and decreased incidence of central core of eosinophilic material with increased incidence of mineralization and focal epidermal hyperplasia compared to PTFE and placebos (MgS and MgS with TCA). Necrosis was variable across BICX-102 implant sites. In general, the single BICX-102 implant had variably increased necrosis compared to single PTFE implant and placebos, while the double BICX-102 implant sites had decreased necrosis when compared to the double PTFE implant. The effect of inherent instability and mechanical trauma of double implants on the necrosis in the double implantation sites was uncertain. Table 26: BICX-102/BICX-104 Comparison Day 182±2 Males BICX-102 4

epresented as number present Table 27: BICX-102/BICX-104 Comparison Day 182±2 Females BICX-102 4

[0092] At Day 91±2, test article-related microscopic findings associated with BICX-102, double BICX-102, or BICX-104 implants consisted of variable inflammation (with leukocyte population of varying severity), necrosis (notably increased in BICX-102 implant conditions), fibrosis, hemorrhage, erosion/ulceration, serocellular crust formation, and the presence of bacterial colonies when compared to control skin, magnesium stearate (MgS) placebo, triamcinolone acetonide (TCA) placebo, and PTFE sham implant. Test article-related systemic microscopic findings were limited to the adrenal gland and thymus of Group 5 animals. Minimal to moderate adrenocortical atrophy and mild to marked thymic lymphoid depletion were identified microscopically, correlating with decreased organ weights in this group. These findings in Group 5 are likely systemic manifestations related to the increased, cumulative dose of triamcinolone acetonide (TCA) present in implants. [0093] BICX-104 implant has been established as a no observable adverse effect level (NOAEL) in Yucatan minipigs. The establishment of the NOAEL was based on the absence of any systemic effects and upon the non-adversity of the microscopic findings. D. Alternative Formulations [0094] Cholesterol in an implant slows the release of the naltrexone active ingredient. An amount of cholesterol is chosen to balance the rate of release of the naltrexone from the pellet into the bloodstream of the patient over the lifetime of the pellet and to minimize the amount of remaining cholesterol in the pellet after all or most of the naltrexone is released. That is, for a given indication, the amount of cholesterol in the implant or pellet is chosen such that there is not an excess of cholesterol remaining toward the end of a lifetime of the pellet such that a less than ideal or preferred amount of naltrexone is released into or absorbed into the bloodstream of the patient toward the lifetime of the pellet (e.g., too much cholesterol may inhibit the sustained release of naltrexone). At the same time, for a given indication, an amount of cholesterol in the implant or pellet is chosen such that enough cholesterol remains surrounding the pellet of naltrexone to allow for a desired release or absorption of naltrexone over the lifetime of the pellet (e.g., too little cholesterol may result in too high of a release of naltrexone at any given point in time during the lifetime of the pellet, and especially toward the lifetime of the pellet). Pellets having 10% or more of cholesterol may lead to an increase in remnant residue in a patient as well as an undesirable increase in total pellet mass (e.g., this may inhibit a more desirable smaller pellet without an added benefit). It is recommended that less than 10% of the implant consist of cholesterol, preferably around 2%. An embodiment of the present invention consists of an implant comprised of 0.1 to 5.0 grams ± 5% by weight, between 1.0 and 1.5 ± 5% by weight, or between 200 mg and 500 mg ± 5% by weight, of naltrexone base, 2 mg magnesium stearate and 4 mg cholesterol with or without 2 mg triamcinolone acetonide (TCA), preferably without triamcinolone acetonide (TCA). If triamcinolone acetonide (TCA) is present in the formulation, the acetonide form is used in amounts ranging from 0.1 to 100 mg ± 5%. A preferred embodiment of the present invention consists of an implant comprised of 200 mg of naltrexone base, 2 mg magnesium stearate and 4 mg cholesterol with or without 2 mg triamcinolone acetonide (TCA), preferably without triamcinolone acetonide (TCA). [0095] Example pellets of the present disclosure may comprise less than 10% cholesterol by weight. Some implants comprise less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% cholesterol. Some implants comprise 0.5%, 1%, 1.5%, 2%. 2.5%. 3%, 3.5%, 4%, 4.5, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, or 9.5% cholesterol. Some embodiments comprise 2% cholesterol. Some embodiments comprise 1% magnesium stearate, 1% triamcinolone acetonide (TCA), and 2% cholesterol. Some implants/pellets comprise a cholesterol coating. Some implants/pellets comprise a partial coating of cholesterol on the exterior of the implant/pellet to slow an initial burst of the naltrexone active ingredient. Some embodiments comprise 1% magnesium stearate, 1% triamcinolone acetonide (TCA) and 2% cholesterol. Some embodiments comprise 200mg naltrexone base, 2mg triamcinolone acetonide (TCA) (steroid active ingredient), 2mg magnesium stearate, and 4mg cholesterol. [0096] In some embodiments, the implant releases dosage amount(s) of naltrexone into a bloodstream of the patient. In embodiments, the dosage amount(s) of naltrexone can be in an amount within the range of 150mg to 5g. In some embodiments, the dosage amount(s) of naltrexone is in an amount of 200mg, 400mg, 1g, 1.1g, 1.2g, 1.3g, 1.4g, or 1.5g. In some embodiments, the dosage amount(s) of naltrexone is in an amount of 2.2g. The amount of naltrexone in a pellet varies from 150mg to 5g naltrexone per pellet and more usually from 200mg -1.4g per pellet. Some pellets comprise 200mg, 400mg, 1.1g, or 1.4 naltrexone. In some embodiments, the dosage amount(s) of naltrexone can be in an amount within the range of 250mg to 4g, 300mg to 4g, 350mg to 4g, 400mg to 4g, 450mg to 4g, 500mg to 4g, 550mg to 4g, 600mg to 4g, 650mg to 4g, 700mg to 4g, 750mg to 4g, 800mg to 4g, 850mg to 4g, 900mg to 4g, 950mg to 4g, 1g to 4g, 1.1g to 4g, 1.5g to 4g, 2g to 4g, 2.2g to 4g, 2.2g to 3g, 2g to 3g, 1.1g to 3g, 1g to 3g, 950mg to 3g, 900mg to 3g, 850mg to 3g, 800mg to 3g, 750mg to 3g, 700mg to 3g, 650mg to 3g, 600mg to 3g, 550mg to 3g, 500mg to 3g, 450mg to 3g, 400mg to 3g, 350mg to 3g, 300mg to 3g, 250mg to 3g, 200mg to 3g, 200mg to 2g, 250mg to 2g, 300mg to 2g, 350mg to 2g, 400mg to 2g, 450mg to 2g, 500mg to 2g, 550mg to 2g, 600mg to 2g, 650mg to 2g, 700mg to 2g, 750mg to 2g, 800mg to 2g, 850mg to 2g, 900mg to 2g, 950mg to 2g, 1g to 2g, 1.1g to 2g, 1.5g to 2g. [0097] Non-limiting examples of dosage amount(s) of naltrexone in the presently disclosed implant include any dosage or amount in increments and/or combinations of 50mg, 100mg, 150mg, 200mg, 400mg, 500mg, 1g, 1.1g, 1.4g, and the like. It will be appreciated that dosages or amounts incrementally between those described above are within the scope of the present disclosure. [0098] The subcutaneous medical implant may comprise a single implant unit (or otherwise referred to as a pellet) configured to release a dosage amount of the naltrexone into a bloodstream of the patient. For example, for a subcutaneous biodegradable medical implant configured to release a dosage amount of 400mg of naltrexone into a patient’s bloodstream, a single 400mg biodegradable naltrexone pellet may be used. [0099] The subcutaneous medical implant may comprise a plurality of implant units configured to release a dosage amount of the naltrexone into a bloodstream of the patient. In some embodiments, the subcutaneous biodegradable medical implant comprises two or more implant units (or otherwise referred to as pellets). For example, for a subcutaneous biodegradable medical implant configured to release a dosage amount of 400mg of naltrexone into a patient’s bloodstream, two (2) 200mg biodegradable naltrexone pellets may be used. [0100] In one embodiment of the claimed invention, the implant may further comprise an outer sheath surrounding an inner core containing the naltrexone active agent. The outer sheath purpose is to separate the naltrexone core from the tissues of the human patient surrounding the implant once it is situated within the patient. Ideally, the outer sheath is inert. The sheath must be biodegradable allowing for the controlled, sustained, and/or gradual release of the naltrexone over an extended period of time. The outer sheath may partially coat the inner core, such as coating ninety percent or less of the inner core, eighty percent or less, seventy five percent or less, seventy percent or less, sixty five percent or less, sixty percent or less, fifty five percent or less or fifty percent or less. In a preferred embodiment, the outer sheath is cholesterol that is applied by dipping, spraying, brushing or spreading the cholesterol onto the outer surface of the naltrexone core. The release of the naltrexone over an extended period of time produces a local or systemic effect in the patient. E. Shape, Number, and Insertion of Naltrexone Implants [0101] In some embodiments, the subcutaneous biodegradable medical implants comprise one or more pellets formed of naltrexone and cholesterol in amounts described herein. In some embodiments, the present implants are tablet shaped, capsule shaped, rod-shaped, spherical, or cylindrical in shape. In some embodiments, the implants are approximately spherical in shape, wherein the diameter and height are approximately the same. In other embodiments, the implants are cylindrical are shaped like a rod. In other embodiments, the implants may further comprise a “bellyband.” Regardless of the shape of the implants, they may have rounded edges, rounded ends, flat edges and/or flat ends. [0102] Rate of release of naltrexone from the implant(s) into the patient’s bloodstream is also varied by shape and number of pellets in a patient’s treatment regimen. For example, an approximately spherical shaped pellet, with a smaller surface area than a rod-shaped pellet of the same volume, would release naltrexone more slowly than a rod-shaped pellet of the same volume. For example, implanting a single larger pellet would result in slower naltrexone release than multiple smaller pellets comprising the same total naltrexone dose as the single larger pellet. [0103] Some treatment regimens utilize pellet shapes and sizes which are compatible with smaller patient incisions (e.g., incisions through which the pellets are subcutaneously placed within the patient body). Some patient incisions are closed with stitches or with 3M® Steri- Strips™ (3M® Company, St. Paul, MN). In some patients, smaller incisions and closure of incisions with Steri-Strips result in reduced pain for the patient from the procedure. [0104] The subcutaneous biodegradable medical implant may be placed, injected, or inserted below a skin surface of the patient or may be placed or injected above a muscle fascia of the patient. [0105] In embodiments of the present disclosure, an implant comprising naltrexone is placed, injected, or inserted beneath a surface of the skin in a lower abdominal area or hip area or other area of a patient. In some embodiments, the subcutaneous biodegradable medical implant is placed below a skin surface of a lower abdomen of the patient. In some embodiments, the subcutaneous biodegradable medical implant is placed below a skin surface of one or more of a hip, a leg, a back, and an arm of the patient. In some embodiments the implants disclosed herein are placed below a skin surface of a patient and above a muscle fascia of the patient. It will be appreciated that a placement location within a patient for a subcutaneous biodegradable medical implant is not limited to the examples herein and may vary according to a given indication or treatment plan. F. Release into Bloodstream and Biodegradation of Pellets, Dosage Frequency [0106] In embodiments, the subcutaneous biodegradable medical implant biodegrades in the patient. In some embodiments, the subcutaneous biodegradable medical implant biodegrades after a period of about 30 days in the patient. In embodiments, the subcutaneous biodegradable medical implant biodegrades over a period of about several months in the patient. [0107] In an example, naltrexone is released from the implant into the bloodstream of a patient over a period of about 4 weeks to one year. In an example, naltrexone is released from the implant into the bloodstream of a patient over a period of about 4 weeks, 5 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or one year. In an example, the implant biodegrades after a period of about 30 days, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or one year in the patient. It will be appreciated that the time it takes to for an implant to biodegrade in a patient is dependent upon multiple factors including dosage, patient metabolism, external activity, and the like. In some embodiments, a second subcutaneous biodegradable medical implant is placed into a patient subsequent to a biodegradation time of a first subcutaneous biodegradable medical implant. [0108] Exemplary timing of implants being inserted into a patient includes once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 13 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, once every 12 months, once a year, or according to any other schedule determined by empirical analysis. Alternatively, insertions of naltrexone implants can be on an irregular basis as indicated by monitoring of symptoms of an addiction disorder, or by monitoring weight changes. It will be appreciated that, according to any given indication, a single insertion of a naltrexone implant described herein may be preferred (e.g., that is, replacement of the implant is not necessary to remain within the scope of the present disclosure). G. Exemplary Placement of Naltrexone Implant in a Patient [0109] In an example, the subcutaneous biodegradable medical implant is placed in a patient according to FIG. 10. [0110] FIG. 10 is a diagram of an exemplary subcutaneous implant placed in a patient according to embodiments of the present disclosure. In embodiments of the present disclosure, a subcutaneous biodegradable medical implant comprising naltrexone 201 is placed into a patient 200. It will be appreciated that, while implant 201 is shown as having been placed into an abdominal area of patient 200, embodiments including placement of the implant into other areas of patient 200 are within the spirit of the present disclosure (e.g., lower abdominal area, hip area, as shown in FIG. 10. It will also be appreciated that implant 200 is not drawn to scale in FIG. 10. Preferably, the implant is implanted subcutaneously into the abdominal or pubic areas of the patient, more preferably, the lower abdominal. In yet another embodiment, the implant is implanted subcutaneously either above or below the patient’s waistline and to the right or to the left of the patient’s mid-line or directly above or below the belly button. In a further embodiment, the implant is implanted into the hip of the patient. In other embodiments, the implant is implanted subcutaneously into a patient so as to be orientated relatively parallel to the ground, wherein said implant orientation reduces mechanical irritation caused by the implant when the patient sits or bends forward. [0111] The inventors of BICX-104 discovered that a preferred embodiment of the instant invention is delineated in a unique method of pellet implantation that preserves a biological tissue zone, i.e., a “tissue bridge,” between two or more pellets. Prior to this discovery, BICX- 104 was observed to erode in the patient after subcutaneous implantation releasing a “zone” of naltrexone and magnesium stearate resulting in a decrease in concentration of the naltrexone as the distance from the surface of the implant increase. In addition, due to increased concentrations of magnesium stearate at the implantation site, local adverse effects were observed as such reactions are concentration dependent. [0112] The inventors of the claimed invention discovered that the use of two pellets positioned in the patient according to a particular scheme improved release of the therapeutic agent. In particular, BICX-104 pellets need to be inserted using a unique method to narrowly ensure a minimum biological zone separation to prevent overlap. The inventors of the instant method discovered that the placement of BICX-104 pellets without a biological zone between the implanted pellets, resulted in increases of local adverse effects due to an increase in local inflammation due to the increase concentration of the magnesium stearate and triamcinolone acetonide in the overlapping zone. FIG. 11 illustrates the insertion procedure and placement of one or, preferably, two BICX-104 pellets in a patient. If only one pellet is inserted, then a single tunnel is formed with the one pellet inserted therein (A or B) via an incision. Preferably, two pellets are inserted into the patient, two tunnels are formed and one pellet is inserted into each of the tunnels. The inventors of the instant invention discovered that a four to five (4-5) centimeter “tissue bridge” between the two pellets inserted into the two tunnels resulted in improved pharmacokinetics of the drug. The preferred embodiment requires two separate implantation pathways from one common initial incision. A single incision reduces procedural adverse events while controlling tissue placement. Not only does this unique discovery extend the life-span of the pellets, while ensuring maximum potency and further distribution of the active agent, it also reduces the number of incisions for the patient and ameliorates local inflammation resulting in fewer noticeable side effects. [0113] The center of a BICX-104 pellet is considered when situating the implant in the patient, i.e., the “center” of placement. In the preferred embodiment, BICX-104 is approximately one centimeter (1 cm) in length and width, but is not necessarily spherical. Accordingly, there is a half a centimeter (0.5 cm) distance from the center of the preferred embodiment to an outer edge of the pellet. As discussed above, taking into account the length of the recommended “tissue bridge,” i.e.., four (4) centimeters, maintained between neighboring pellets, the inventors of the claimed method, suggest a distance of five centimeters (5 cm) between the “centers” of neighboring pellets. Taking these recommendations into consideration, with each pellet preferably inserted into the patient at a distance of five centimeters (5 cm) from the incision site along tunnels “A” and “B”, as depicted in FIG. 11, the preferrable angle between tunnels “A” and “B” is recommended to be from 60⁰ to 300⁰ in order to ensure the optimal “tissue bridge” minimally of four centimeters (4 cm) between the two inserted BICX-104 pellets, thus insuring minimal overlap with little or no observable adverse inflammatory reactions. This novel approach to implant placement to reduce adverse responses is supported by histological analysis of the BICX-104 implantation sites of the animal models as well as observations of human implantation sites for human clinical trials. [0114] A subcutaneous biodegradable medical implant may be inserted using an insertion device (e.g., a syringe, an applicator, a trocar, or any other appropriate insertion device). H. Storage [0115] The implants of the present invention may or may not be terminally sterilized before or after the implants are packaged transportation and long-term storage. If the pellets are sterilized, the preferred sterilization processes are gamma sterilization or e-beam sterilization. It is recommended that if gamma sterilization is selected that it be applied at a strength ranging from 25 eV to 40 eV ±5%. The pellets, are typically stored in a sealed container, such as, but not limited to, a syringe, bottle, vial, blister pack or cartridge, which is typically suitable for long term storage, i.e., a “first storage means.” "Suitable for long-term storage" means that the syringe, bottle, vial, blister pack or cartridge, does not allow for the escape of components of the pellets of the present invention or the ingress of external components, such as, microorganisms during long-term storage. After the pharmaceutical formulation is loaded into the first storage means, the first storage means may be sterilized and the sterilized first storage means may be stored in a second storage means, such as a pouch, vacuum-sealed wrapping, or any other storage means known in the art. I. Pharmacokinetic Profile of BICX-104 [0116] The preferred embodiment was the subject of preclinical pharamacokinetic (PK) studies using a Yucatan pig model. From these studies, the inventors of the present method discovered the need for two, not one, BICX-104 pellets are required for optimal treatment of a patient in need of treatment. In particular, the preclinical data showed a minimum effective concentration greater than one nanogram of naltrexone per milligram of plasma was sustained until day ninety-one (91) single one (1) BICX-104 pellet in approximately forty (40) kilogram Yucatan pig. Yucatan pigs weighing forty (40) kilograms are not representative of the anticipated human population weighing eighty (80) kilograms. Based on the study data reported in Tables 28 and 29: Table 28: Cmax Preclinical Study of BICX-104 in a 40kg Yucatan Pig Model

Table 29: Single Dose BICX-104 PK (Cmax) Profile (mean ± SD) in a Yucatan Pig Model Cmax Tmax AUCTlast AUC0-7day AUC0-28day AUC0-90day 31.7 0.5 362 ± 83.5 106 ± 28.2 235 ± 46.8 361 ± 77.3 4 ’.

, CX- 104 pellets are required. FIG. 12 plots the data reported in Table 28 as a graph of mean serum concentration in nanograms per ml (ng/ml) against time. As evidenced in Table 29, the naltrexone levels in the pig study drop from 6.58 ng/ml (100%) on Day 13 to 3.76 ng/ml (57%) on Day 27 to 2.34 ng/ml (35%) on Day 55. [0118] Human clinical studies employing two BICX-104 pellets, demonstrated a minimum effective concentration of naltrexone of greater than one nanogram per milliliter (>1ng/ml) was sustained up to and including day 84 (C84) as reported in Table 30 below: Table 30: PK Profile for Administration of Two (2) BICX-104 Pellets in Human Clinical Trials Using Healthy Volunteers

[0119] The observations made in human volunteers are consistent with the data collected during the Yucatan pig studies. FIG. 13 plots the data reported in Table 30 as a graph of mean serum concentration in nanograms per ml (ng/ml) against time. [0120] The inventors of the claimed method observed that the Cmax for BICX-104 in the Yucatan pig model from one pellet was equal to 31.7 ng/ml. Accordingly, the inventors anticipated that two pellets implanted in human volunteers would generate a similarly high Cmax. The Cmax values observed in volunteers receiving two (2) BICX-104 pellets were equal to 19.91 ng/ml. This level is significantly lower than predicted by Yucatan animal data or prior art. [0121] In other naltrexone implants known in the art that have a similar composition and mass of naltrexone, there is a classical pharmacokinetic signature that is delineated by three phases of first order kinetics of ingredient release; a). an initial burst release that causes an initial and transient spike; b). a second hydration stage that is characterized by a pronounced release of ingredient over the first few days or weeks, followed by a c). lag phase of slow steady release at low concentrations. BICX-104 has a unique pharmacokinetic signature that is unexpected and surprising. In addition, the design of BICX-104 provides special characteristics that differentiate BICX-104 from prior art naltrexone formulations. These attributes give BICX-104 surprising utility. Comparatively, the known naltrexone formulations are characterized by obtaining relatively low concentrations of the drug quickly after the second hydration phase. Natrexone’s therapeutic efficacy is based upon attaining therapeutic concentrations. A minimum effective concentration is widely considered to be 1 ng/ml. Higher concentrations are associated with greater efficacy due to both the ability to compete with mu opioid receptor occupancy with deleterious agonists in opioid use disorder and in eliciting maximal anti-craving effects. [0122] BICX-104 is delineated by the unique pharmacokinetic signature that was observed in Phase 1 clinical trials in Healthy Volunteers. J. Pharmacokinetic Profile of Vivitrol® [0123] Vivitrol® (Alkermes®, Waltham, MA) ((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)- 4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one incorporated in a ratio of 75:25 into polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres and a diluent comprised of carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water) is the leading, long-acting injectable form of naltrexone. Vivitrol® is used as part of a treatment program to prevent alcohol or opioid dependence. Vivitrol® is an opioid antagonist that blocks mu opioid receptors and by changing how the hypothalamus, pituitary gland and adrenal glands work together. Vivitrol® blocks the intoxication and euphoria or 'high' that alcohol and opioids cause as well as the pain relief that opioids provide. Vivitrol® is an extended-release suspension that is injected into the gluteal muscle. Once injected, it slowly releases naltrexone (the active ingredient) for about a month. Vivitrol® was first approved by the US Food and Drug Administration in 2006. [0124] It has been reported (ClinicalTrials.gov Identifier: NCT01218971) that after a 1M administration of Vivitrol®, peak plasma levels of naltrexone were observed in about five (5) hours to two (2) days. The increase in area under the curve (AUC) of naltrexone was approximately dose-proportional in the range of 141-784 mg Vivitrol® (study # ALK21-001, - 002). Naltrexone elimination appears to be release rate-dependent as the elimination half-life for the product is approximately eight (8) days, while oral naltrexone has a five (5) hour half-life (ClinicalTrials.gov, (2010), :ALK21-003EXT: An Extension of Study ALK21-003 (NCT01218958) to Test the Long-term Safety of Medisorb® Naltrexone (VIVITROL®),” National Library of Medicine, ClinicalTrials.gov Identifier: NCT01218971, (7 pages)), the results are reported in FIG. 14 and the Cmax values measured against time are reported in Table 31 below:

Table 31 – Cmax Values Reported for Vivitrol^®

[0125] The PK characteristics of the Vivitrol® 380mg naltrexone depot formulation demonstrates a typical high Cmax followed by a sharp drop in naltrexone concentrations to a low level that are sustained for the duration of the implants performance. BICX-104 is atypical to this characteristic. The PK profile of BICX-104 is unique and atypical; even in comparison to oral dosage form of 50mg naltrexone (Dean, R.L. (2009), Nonclinical Pharmacology of VIVITROL^®: A Monthly Injectable Naltrexone for the Treatment of Alcohol Dependence. In: Dean, R.L., Bilsky, E.J., Negus, S.S. (eds) Opiate Receptors and Antagonists. Contemporary Neuroscience. Humana Press, (pp. 655-74)) as shown in FIG. 18. As shown, the oral tablets PK profile is also characterized by an initial Cmax spike that falls off rapidly to a sustained low concentration. [0126] The inventors of the claimed invention observed that the Cmax for BICX-104 is also lower than the Cmax reported for the Vivitrol® 380mg intramuscular injections. Despite the Vivitrol® 380mg dose being 38% of the total BICX-1041000mg dose, the Cmax of Vivitrol® is 12.4ng/ml; 9.36ng/ml and 9.96 ng/ml, for each of three consecutive injections in the same Phase 1 clinical study as BICX-104. Therefore, the Cmax of Vivitrol® is 62.3%; 47% and 50%; a significantly lower Cmax for BICX-104 than predicted by the prior art or even cross comparison to Vivitrol® that uses a sustained release modality to blunt its own Cmax in addition. [0127] Accordingly, a BICX-104 pellet has a Cmax release character that is inconsistent with the prior art; the preclinical animal data and the teachings of the prior art, anticipated a Cmax was observed that was closer to the 31.7ng/ml level observed in pigs or the levels reported in the prior art. The specific embodiment of BICX-104, that teaches away from the high Cmax that was expected, is an improvement because a lower Cmax, both locally and systemically, results in a concomitant decrease in frequency and severity of dose limiting adverse events. [0128] In a specific embodiment, a single 84 day treatment course of BICX-104 provided a highly adherent treatment over 84 days, whereas 28-day Vivitrol® 1M injections provided three times over 84 days demonstrated low adherence, especially in female subjects. J. Prodetoxone® and BICX-104 Single Subcutaneous Animal Studies [0129] Prodetoxone® (Fideliti Capital, Moscow, RU) has a blocking effect on opiate receptors. The active agent is naltrexone proven to reliably block opiate receptors in the brain for a notable duration. Narcotic substances, such as opium, heroin, methadone, and analgesics of

Prodetoxone® has also been reported to suppress the effects of alcohol on the human body. Prodetoxone®. [0130] The Inventors of the instant application discovered that a combination of Prodetoxone® and BICX-104 delivered subcutaneously (s.c.) provides constant and long-term maintenance of N-telopeptide (NTx) plasma concentrations for at least two (2) months after administration. Pharmacokinetic (PK) evaluations were carried out on Wistar™ IGS rats, (n=6; 200-230g)(Charles River Laboratories, Wilmington, MA) and dogs, (n=6; 14.2-15.3 kg) (Charles River Laboratories, Wilmington, MA). Depot implants of 0.016g in rats and 1.0g in dogs, at 5- times the clinical therapeutic dose of71.5mg/kg, were implanted subcutaneously in the cervical region of both animals.7-Benzylidenenaltrexone (BNTX) concentration was analyzed after 1, 2, 3, 4, 5, 7, 10, 15, 18, 20, 25, 30, 45 and 60 days by high-performance liquid chromatography (HPLC). The results are reported in FIG. 15. Additionally, general condition, behavior, speed of healing, and biochemical analyses was carried out throughout the study for each animal. This is further embodied by comparison with the PK profile of the Prodetoxone® 1 gram naltrexone pellet as illustrated in FIG. 17. Naltrexone concentrations are sustained in every patient at a steady level that is clearly differentiated from the atypical pH of BICX-104. [0131] In other known naltrexone implants of similar composition and mass, classic pharmacokinetic signatures have been reported that are defined by three phases of first order kinetics ingredient release: an initial burst release that causes and initial and transient spike; a second hydration stage that is characterized by a pronounced release of ingredient over the first few days or weeks; and a third lag phase of slow steady release at low concentrations. BICX- 104 has a unique pharmacokinetic signature that is surprising resulting from the manufacturing process for BICX-104. Naltrexone release in prior art formulations is characterized by reaching relatively low concentrations quickly after the second hydration phase. Naltrexone’s therapeutic efficacy is based upon attaining therapeutic concentrations. A minimum effective concentration is widely considered to be one 1 ng/ml. As it will be understood by one of skill in the art, higher concentrations of a pharmaceutical in the patient are associated with greater efficacy due to both 1) the ability to compete with mu opioid receptor occupancy with deleterious agonists in opioid use disorder; and 2) the ability to elicit maximal anti-craving effects. [0132] BICX-104 has a pharmacokinetic release that preserves and maintains the release of naltrexone at high levels for sustained periods of time without inducing a dangerous initial burst or a hydration phase maximal release that can be dose limiting due to increased incidence or severity of adverse events. As shown in FIG. 14, the plasma concentrations observed in the animal models at day 14 was reported to be 17.23 ng/ml (100%); at day 28 a concentration of 11.32 ng/ml (65%) was recorded and at day 56 a concentration of 6.85 ng/ml (40%). As can be appreciated by those of skill in the art, concentrations are uniquely high and sustained, the reported concentration evidence that BICX-104 elicits potent pharmacological effects in patients. [0133] The pharmacokinetic potency reported for BICX-104 is not described in prior art formulations on naltrexone and is a unique attribute of BICX-104 that was not expected. [0134] Similar results for BICX-104 were also observed in pig studies, the naltrexone levels in pig study drop from Day 13 at 6.58ng/ml (100%) to Day 27 at 3.76 ng/ml (57%) then at Day 55 at 2.34 ng/ml (35%). Therefore, some unexpected results and unpredictable convergence of physiology and BICX-104 resulted in the unique PK behavior that imparts sustained naltrexone levels without deleterious maximal concentrations. K. Wedgewood® Implant Studies and Other Implants Compared to BICX-104 [0135] In other naltrexone implants known in the art that have a similar composition and mass of naltrexone to that of BICX-104, there is a classical pharmacokinetic signature that is delineated by three phases of first order kinetics ingredient release: an initial burst release that causes and initial and transient spike; a second hydration stage that is characterized by a pronounced release of ingredient over the first few days or weeks; followed by a third lag phase of slow steady release at low concentrations. BICX-104 has a unique pharmacokinetic signature that is a surprising product of its manufacturing and dimensions that differentiates BICX-104 from prior art and provides unique and surprising utility. [0136] Naltrexone release in prior art formulations is characterized by reaching relatively low concentrations quickly, after the second hydration phase. Naltrexone’s therapeutic efficacy is based upon attaining therapeutic concentrations. A minimum effective concentration is widely considered to be 1ng/ml. As it will be to one skilled in the art, higher concentrations are associated with greater efficacy due to both 1) the ability to compete with mu opioid receptor occupancy with deleterious agonists in opioid use disorder and 2) in eliciting maximal anti- craving effects in many disorders. As evidenced in Table 29, the naltrexone levels in the pig study drop from 6.58 ng/ml (100%) on Day 13 to 3.76 ng/ml (57%) on Day 27 to 2.34 ng/ml (35%) on Day 55. [0137] Another prior art implant, the Wedgewood^® Implant (Wedgewood^® Pharmacy, Sewell, NJ, USA) containing 1.4 grams of naltrexone with magnesium stearate exemplifies the disparity between BICX-104 and implants of this type. As evidenced in FIG. 16, the Wedgewood^® implant’s PK profile drops rapidly after initial implantation and maintains a low concentration of naltrexone; typical of such implants. As shown in FIGs. 12 and 13, BICX-104 is surprisingly atypical in that the naltrexone plasma concentrations do not drop rapidly, but do so in a slow and linear fashion, maintaining high and more therapeutic concentrations of naltrexone for longer. In the preferred embodiment, this lack of a precipitous drop in naltrexone concentrations in the BICX-104 invention is further beneficial to patients because the patients do not experience a rapid loss of therapeutics effects and such effects are sustained for significantly longer. Therefore, some unexpected and unpredictable convergence of physiology and BICX- 104 resulted in the unique PK behavior that imparts sustained naltrexone levels without deleterious maximal concentrations. [0138] The PK characteristics of the naltrexone subcutaneous bead that is a solid solution sphere with a 1.5 mm diameter and being 3.0 mg in weight is composed of 70% naltrexone in a physical blend with a copolymer of 90% L(+)-lactic acid and 10% glycolic acid (Chiang CN et al., (1984), “Kinetics of Naltrexone Sustained-Release Preparation, Clin Pharmacol Ther, 36(5):704-8). As shown in FIG. 19, plasma concentrations drop precipitously from a Cmax high and then plasma concentration are sustained at a low level over a longer period of time. L. Combination Therapy [0139] It has been reported that there are certain addicts that do not respond to naltrexone (Anton RF et al., (2011), Am J Psychiatry, 168(7):709-17). In addition, there is also the possibility that a patient who is treated with Vivitrol^® could overcome the opioid blockade effect of Vivitrol^®. Although Vivitrol^® is a potent antagonist with a prolonged pharmacological effect, the blockade produced by Vivitrol^® is surmountable. In some embodiments of the present invention, the inventors found that a combination therapy comprising Vivitrol^® and BICX-104, due to the unique pharmacokinetic signature for BICX-104, was an option when the effects of Vivitrol^® waned in the patient. In some embodiments, the invention provides a medicament comprising commercially available opioid antagonists, such as Vivitrol^® or Prodetoxone^®, for use in combination with BICX104 for treating addiction. The combination medicament would be administered prior to ceasing the administration of the Vivitrol^® or Prodetoxone^® so as to wean the patient off of either leading to the sole administration of BICX-104. The reverse is possible in the event that BICX-104 becomes less effective. [0139] In another embodiment, the present invention is directed to a method of making a medicament comprising BICX-104 and Vivitrol^® and/or Prodetoxone^® using the same procedures discussed above. M. Conclusion [0140] Many modifications and other embodiments of the disclosures set forth herein will come to mind to one skilled in the art to which these disclosures pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

We claim: 1. A pharmaceutically-acceptable implant consisting of (4R,4aS,7aR,12bS)-3- (cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2- e]isoquinolin-7-one or salts thereof or anhydrous bases thereof or prodrugs thereof, and magnesium stearate in an amount equal to 0.011 grams ±5% by weight; and wherein the implant is designed to be subcutaneously implanted so as to be orientated relatively parallel to the ground. 2. A pharmaceutically-acceptable implant consisting of (4R,4aS,7aR,12bS)-3- (cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2- e]isoquinolin-7-one or salts thereof or anhydrous bases thereof or prodrugs thereof, and magnesium stearate in an amount equal to 0.011 grams ±5% by weight; and wherein the implant is designed to be subcutaneously implanted in a pair at the same location with a biological tissue zone separating the two implanted implants; and wherein the pair of subcutaneously implanted implants do not overlap. 3. The pharmaceutically-acceptable implant according to claim 2, wherein each of the pair of implants is inserted into two separate implantation pathways from one common initial incision. 4. The pharmaceutically-acceptable implant according to claim 2, wherein each of the pair of implants is inserted into two separate implantation pathways wherein the biological tissue zone separating the two implanted implants has a width of between four and five centimeters. 5. The pharmaceutically-acceptable implant according to claim 4, wherein the two separate implantation pathways are at an angle to each other. 6. The pharmaceutically-acceptable implant according to claim 4, wherein the angle between the two separate implantation pathways ranges from 60° to 300°. 7. A pharmaceutically-acceptable implant designed to treat an opioid use diorder, comprising (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro- 1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one or salts thereof or anhydrous bases thereof or prodrugs thereof, and magnesium stearate in an amount equal to 0.011 grams ±5% by weight; and ((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinolin-7-one) incorporated in a ratio of 75:25 into polylactide-co- glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres and a diluent comprised of carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water.