Summary of The Invention
The present invention provides a composition for the controlled release of a substance comprising: (i) a non-polymeric, water-insoluble High Viscosity Liquid Carrier Material (HVLCM) having a viscosity of at least 5,000 centipoise at 37 ℃ that does not crystallize neat under ambient or physiological conditions; and (ii) a substance to be delivered.
In particular, the present invention provides a composition for the controlled release of a biologically active substance comprising:
(a) a non-polymeric, water-insoluble liquid carrier material having a viscosity of at least 5,000 centipoise at 37 ℃ that does not crystallize neat under ambient or physiological conditions; and
(b) a biologically active substance.
The present invention also provides an emulsion for the controlled release of a biologically active substance comprising:
(a) a non-polymeric, water-insoluble liquid carrier material having a viscosity of at least 5,000 centipoise at 37 ℃ that does not crystallize neat under ambient or physiological conditions; and
(b) a biologically active substance contained in an aqueous-based carrier.
In one embodiment, the HVLCM is mixed with a low viscosity water-soluble or water-miscible solvent such as ethanol, dimethyl sulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate, hydrofurfuryl polyethylene glycol ether (glycofurol), freons such as trichlorofluoromethane and dichlorofluoromethane, dimethyl ether, propane, butane, dimethylformamide, dimethylacetamide, diethyl carbonate, butylene glycol, N- (. beta. -hydroxymethyl) lactamide, diokoolanes, and other amides, esters, ethers, alcohols, and the like, to form a Low Viscosity Liquid Carrier Material (LVLCM) that is mixed with the substance to be delivered prior to application. In a preferred embodiment, the viscosity of the LVLCM is less than 1000 centipoise. Upon administration, the composition is placed in the body or applied to the body surface, and the solvent dissipates or diffuses from the LVLCM, forming a high viscosity implant or composition in situ that releases the delivered substance over time. By appropriate choice of solvent and HVLCM, the viscosity of the composition can be made to be very different before and after application. In a preferred embodiment, the HVLCM is biodegradable.
In one embodiment, the substance mixed with the HVLCM is a biologically active substance useful for human therapy, veterinary therapy, or for agriculture. For example, in the agricultural field, compositions containing suitable active agents may be sprinkled over the ground to control weeds (e.g., diquat), insects (e.g., methyl parathion), or pests. For example, in veterinary medicine, the compositions may be used to deliver mixed steroids as growth promoters for livestock, or to deliver vaccines (e.g., picornavirus vaccines for the maternal prevention of swine). In the human treatment sector, the compositions can be used to deliver various biologically active substances (described in more detail below), or can be used with or without active agents, for preventing surgical adhesions, or for scaffolding, void filling, or for the generation of tissue-directed renewal products, such as periodontal tissue membranes. In another embodiment, the composition can be injected into the supply artery of a tumor, where a high viscosity implant is formed, preventing blood supply to the tumor. In yet another embodiment, the composition may be used as a tissue adhesive, with or without sutures. In yet another embodiment, the composition may be used as an incomplete occlusive protective layer for wounds.
The in vivo implant of the composition may be placed anywhere in the body, including soft tissues, such as muscle or fat; hard tissue, such as bone; a cavity, including, but not limited to, a periodontal, oral, vaginal, rectal, or nasal cavity; or a capsule, such as a periodontal capsule or an eye cul de sac.
As mentioned above, the composition optionally contains additives that can improve its properties. Non-limiting examples of suitable additives include biodegradable polymers, non-biodegradable polymers, natural or synthetic oils, carbohydrates or carbohydrate derivatives, inorganic salts, BSA (bovine serum albumin), surfactants, and organic compounds, such as sugars and organic salts, such as sodium citrate. In general, the more water-insoluble, i.e., more lipophilic, the additive, the slower the release rate of the matrix, as compared to the same composition without the additive. In one embodiment, it is desirable to employ additives that enhance a property of the composition, such as strength or porosity. In another embodiment, the HVLCM or LVLCM is used in combination with additives without the substrate being delivered.
In yet another embodiment, the HVLCM/substrate composition is contained within a second carrier material to facilitate storage, handling, delivery, or otherwise improve one or more characteristics of the composition. Non-limiting examples of second carrier materials are liquids (forming an emulsion) in which the HVLCM is insoluble, solids, gel formulations, and transdermal delivery systems. The solubility of the matrix in the HVLCM should be high and the solubility in the second carrier material should be low.
For example, an emulsion of HVC 114/matrix in water can be formulated. One practical emulsion of the invention is a mouthwash, wherein the substrate is an active agent for the treatment of halitosis, oral infections, or other oral conditions.
In yet another embodiment, the HVLCM is used as a carrier for topical administration of the matrix. For example, the HVLCM can aid in the solubility of bioactive agents and their transdermal delivery. In yet another embodiment, the HVLCM can be used as a carrier for an insect repellent that contains DEET. In yet another embodiment, the HVLCM is used to deliver a compound, such as a lice-removing or anti-dandruff compound, or a therapeutic compound to the hair or scalp.
Brief Description of Drawings
FIG. 1 is a graph of the release of methylene blue from SAIB (sucrose acetate isobutyrate) as measured in percent release over time (hours) (80% SAIB, closed circle; 85% SAIB, closed downward-pointing triangle; 90% SAIB, open square; 95% SAIB, upward-pointing triangle).
FIG. 2 is a graph of the release of theophylline from SAIB as measured over time (hours) (0.5% theophylline, closed circle; 1.0% theophylline, lower triangle; 2.5% theophylline, closed square; 5.0% theophylline, upper triangle; 10% theophylline, closed diamond).
FIG. 3 illustrates the effect of sucrose on the release of methylene blue from 90% SAIB, as indicated by the percent release over time (hours), (filled circle, 0% sucrose (90% SAIB, 10% ETOH); lower triangle, 2.5% sucrose (90% SAIB, 7.5% ETOH); filled square, 5.0% sucrose (90% SAIB, 5% EtOH)).
FIG. 4 illustrates the effect of CAB (cellulose acetate butyrate) on the release of methylene blue from SAIB, as measured by the percent release over time (hours) (filled circle, 5% CAB (SAIB 40%, ETOH 55%); filled downward-pointing triangle, 10% CAB (SAIB 40%, ETOH 50%); and filled square, 15% CAB (SAIB 40%, ETOH 45%)).
FIG. 5 is a graph of BSA release from a BSA (9%)/SAIB paste, as measured by release (mg released) over time (hours).
FIG. 6 is a graph of the release of chlorhexidine from SAIB/ethyl lactate (EtLac) as measured in percent release over time (hours) (50/50 SAIB/EtLac, open circle; 70/30SAIB/EtLac, open downward-pointing triangle; 90/10 SAIB/EtLac, open square).
FIG. 7 is a graph of the release of chlorhexidine from SAIB/NMP as measured in percent release over time (hours) (50/50 SAIB/NMP, open circle; 70/30SAIB/NMP, open downward-pointing triangle; 90/10SAIB/NMP, open square).
FIG. 8 is a graph of the release of chlorhexidine from SAIB/propylene carbonate as measured in percent release over time (hours) (64% SAIB, open circle; 75% SAIB, open downward-pointing triangle; 85% SAIB, open square).
FIG. 9 is a graph of the release of 2.5% diclofenac (diclofenac) from SAIB/triacetin as measured in percent release over time (hours) (50/50 SAIB/triacetin, open circle; 70/30 SAIB/triacetin, open downward-pointing triangle; 90/10 SAIB/triacetin, open square).
FIG. 10 is a graph of the release of 2.5% diclofenac (diclofenac) from SAIB/ethanol (EtOH) with and without sucrose, as measured by percent release over time (hours) (79% SAIB, open squares; 82% SAIB, closed downward-pointing triangles; 90% SAIB, closed squares; 88% SAIB, open downward-pointing triangles; 88% SAIB, 2.5% sucrose, closed circles; 80% SAIB, 5% sucrose, open circles).
FIG. 11 is a graph of the release of 2.5% diclofenac (diclofenac) from SAIB/EtOH with and without additive, CAB and cellulose acetate propionate ("CAP"), as measured in percent release over time (hours) (no additive, open squares; CAP-containing, open downward-pointing triangles; CAB-containing, open circles).
FIG. 12 is a graph of the release of 2.5% diclofenac from SAIB/Dimethylsulfoxide (DMSO) as measured in percent release over time (hours) (70/30 SAIB/DMSO, open circle; 90/10 SAIB/DMSO, open downward-pointing triangle).
FIG. 13 is a graph of the release of flurbiprofen from SAIB/45% EtOH/5% CAB as measured in percent release over time (hours) (4.99% flurbiprofen, open squares; 9.92% flurbiprofen, closed diamonds).
FIG. 14 is a graph of the release of naproxen (free acid or sodium salt) from SAIB/hydrofurfuryl polyglycol ether (glycofurol) as measured by percent release over time (hours) (73% SAIB, 5.2% naproxen (free acid), open circle; 60% SAIB, 3.6% naproxen (free acid), open downward-pointing triangle; 52% SAIB, 4.1% naproxen (free acid), open square; 74% SAIB, 5.2% naproxen (sodium salt), closed circle; 60% SAIB, 3.4% naproxen (sodium salt), closed downward-pointing triangle; 52% SAIB, 3.9% naproxen (sodium salt), closed square).
FIG. 15 is a graph of the release of 2.5% theophylline from SAIB (40%)/EtOH/CAB or CAP as measured in percent release over time (hours) (5% CAB, open circle; 10% CAB, closed circle; 15% CAB, open downward-pointing triangle; 5% CAP, closed downward-pointing triangle; 10% CAP, open square; 15% CAP, closed square).
FIG. 16 is a graph of theophylline release from SAIB/propylene carbonate as measured in percent release over time (hours) (64% SAIB, open downward-pointing triangle; 74% SAIB, closed circle; 84% SAIB, open circle).
Figure 17 is a release profile of two formulations. One formulation (dark shading) contained 3.2% SAIB, 15.1% ETOH, 0.00395% methylene blue and the remainder deionized water. Another formulation (shading) contained 0% SAIB, 28.9% ETOH, 0.00395% methylene blue and deionized water.
Detailed Description
I. Selection of high viscosity liquid carrier materials
The high viscosity liquid carrier material should be selected to be non-polymeric, water insoluble, have a viscosity of at least 5,000 centipoise (optionally at least 10,000, 15,000, 20,000, 25,000, or even 50,000 centipoise) at 37 ℃, and not crystallize at all under ambient or physiological conditions. The term water-insoluble means that the material has a solubility in water of less than 1% by weight under ambient conditions.
In a preferred embodiment, the HVLCM exhibits a significant decrease in viscosity when mixed with a solvent, resulting in a LVLCM that can be mixed with a substrate for controlled delivery. The LVLCM/matrix composition is generally easier to inject into the body than the HVLCM/matrix composition because it flows more easily into and out of a syringe or other injection tool and can be easily formulated as an emulsion. The LVLCM can have any viscosity desired. It has been found that a LVLCM having a viscosity of less than about 1000 centipoise, and particularly less than 200 centipoise, is generally suitable for use in vivo.
In one embodiment, the HVLCM is a disaccharide ester, such as disaccharide diacetate hexabutyrate.
In a preferred embodiment, sucrose acetate isobutyrate ("SAIB"), a sucrose molecule esterified with two acetic acid moieties and six isobutyric acid moieties, is used as the HVLCM. The structure of SAIB is listed below.
SAIB is not toxic to oral administration, and is commonly used in the food industry to stabilize emulsions. SAIB is a very viscous liquid, characterized by a significant change in viscosity upon slight heating or addition of a solvent. It is soluble in a wide variety of biocompatible solvents. SAIB may be applied by injection or spraying in solution or emulsion. SAIB is miscible with cellulose esters and other polymers that can affect the rate of matrix delivery.
In other embodiments, the HVLCM can be stearates, such as propylene glycol, glycerol, diethylaminoethyl, and ethylene glycol stearates, stearamides and other long chain fatty acid amides, such as N, N' -ethylenedistearamide, stearamide Monoethanolamine (MEA) and stearamide Diethanolamine (DEA), ethylenedistearamide, coconut amine oxide, long chain fatty alcohols, such as cetyl and stearyl alcohols, long chain esters, such as myristyl myristate, behenyl erucate, and glycerophosphate esters. In a particular embodiment, the HVLCM is acetylated sucrose distearate (Crodesta A-10).
The HVLCM is present in the composition in any amount that achieves the desired effect. For example, when used as a tissue protective layer or to prevent adhesions, the HVLCM can be used alone as a protective film or mass, or with a substrate that can enhance the performance or function of the material. The HVLCM is present in the controlled delivery composition in an amount of about 99.5% to about 0.20% by weight. The HVLCM is typically present in the controlled delivery composition in an amount of about 99.5% to about 10% by weight, more typically 95-25%, and most typically 85-45% of the total weight of the composition.
Material to be transported
Any substance exhibiting the desired characteristics may be delivered by the methods described above. Preferably the substance is a biologically active substance.
The term bioactive substance as used herein refers to organic molecules that produce a biological effect when administered to an animal, including but not limited to birds and mammals, including drugs, peptides, proteins, carbohydrates (including mono-, oligo-and polysaccharides), nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, or small molecules linked to proteins, glycoproteins, steroids, nucleic acids (any form of DNA, including CDNA, or RNA, or fragments thereof), nucleotides, nucleosides, oligonucleotides (including antisense oligonucleotides), genes, lipids, hormones, vitamins, including vitamin C and vitamin E, or mixtures thereof.
The term drug as used herein refers to any substance, either internal or external, that is an agent for treating, treating or preventing a disease or disorder, including, but not limited to, immunosuppressants, anti-aging agents, anesthetics, chemotherapeutic agents, steroids (including retinoids), hormones, antibiotics, antiviral agents, antifungal agents, antiproliferatives, antihistamines, anticoagulants, anti-photoblepharmic agents, melanotropins, non-steroidal and steroidal anti-inflammatory compounds, antipsychotic agents, and radiation absorbers, including ultraviolet light absorbers.
The term bioactive also includes agents such as insecticides, pesticides, fungicides, rodenticides, and plant nutrients and growth promoters.
In one embodiment, the composition is a vaccine and the substance to be delivered is an antigen. The antigen may be produced by cells, bacteria, viral particles, or fragments thereof. As described herein, an antigen can be a protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, or mixture thereof, that can elicit an immune response in an animal, e.g., a mammalian bird or fish. As described herein, the immune response may be humoral or cell-mediated. If the substance that elicits the immune response is poorly antigenic, the substance may be bound to a carrier (e.g., albumin) or to a hapten using standard covalent binding methods, such as by a commercially available kit.
Examples of preferred antigens include viral proteins such as influenza proteins, Human Immunodeficiency Virus (HIV) proteins, hepatitis A, B or C proteins, and bacterial proteins, lipopolysaccharides such as gram-negative bacterial cell walls and neisseria gonorrhoeae proteins, and picornaviruses.
Non-limiting examples of pharmacological materials include anti-infective agents such as nitrofurazone, sodium propionate, antibiotics including penicillin, tetracycline, oxytetracycline, chlortetracycline, bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, amikacin, erythromycin and azithromycin; sulfonamides, including sulfacetamide, sulfamethidine, sulfadimidine, sulfadiazine, sulfamethazine and sulfisoxazole, and antivirals including herpotyn; antiallergic drugs such as antazoline, thiapipradine, chlorpheniramine, pyrilamine, phenalenmine, hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, triamcinolone, 6 a-methyl-11 β -hydroxyprogesterone, prednisolone 21-sodium succinate and prednisolone acetate; desensitizing agents such as ragweed pollen antigens, hay fever pollen antigens, dust antigens, and cow milk antigens; vaccines, such as smallpox, yellow fever, febrile diseases, hog cholera, chicken pox, anti-snake toxins, scarlet fever, dyptheria toxoid, tetanus toxoid, pigeon pox, pertussis, rabies, mumps, measles, polio and newcastle disease; decongestants such as phenylephrine, naphazoline, and oxazoline tetrahydrate; miotics and anticholinesterases such as pilocarpine, myricetin salicylate, carbachol, diisopropyl fluorophosphate, diethoxyphosphorylthiocholine iodide and dimehypo bromide; parasympathetic blocking agents, such as atropine sulfate, cyclopentadine, homatropine, scopolamine, tropicamide, eucatropine, and hydroxylated amphetamine; sympathomimetics such as epinephrine, sedatives, and hypnotics, such as sodium pentobarbital, phenobarbital, sodium secobarbital, codeine, (a-bromoisovaleryl) urea, and diethylbromoacetylurea; psychostimulants such as 3- (2-aminopropyl) indole acetate and 3- (2-aminobutyl) indole acetate; sedatives such as reserpine, chlorpromyaline and perphenazine; (ii) an androgenic steroid,such as methyltestosterone and fluoromesterone; estrogen hormones such as estrone, 17- β -estradiol, ethinyl estradiol and diethylstilbestrol; progestational agents such as progesterone, megestrol, mestranol, progesterone chloride, hydrogestrel, norethindrone, 19-norprogesterone, norethindrone, methyl progesterone, and 17-b-hydroxy-progesterone; preparations acting on body fluids, e.g. prostaglandins, e.g. PGE1、PGE2And PGF2(ii) a Antipyretics such as aspirin, sodium salicylate, and salicylamide; antispasmodics such as atropine, etamine, papaverine, and methyl scopolamine bromide; antimalarial drugs such as 4-aminoquinoline, 8-aminoquinoline, chloroquine and pyrimethamine; antihistamines such as diphenhydramine hydrochloride, theanolamine, benzpiramide, perphenazine, and chlorphenazine; cardioactive agents such as dibenzhydroflumethiazide, triflumethine, chlorothiazide, and trinitroethanolamine; nutritional agents, such as vitamins, natural or synthetic bioactive peptides and proteins, including growth factors, cell-linking factors, cytostatins and biological response modifiers.
The active compound is included in the composition in an amount sufficient to deliver an effective amount of the active compound to the subject animal or plant to achieve the desired effect. The amount of drug or bioactive agent contained in the composition depends on the desired release profile, the desired concentration of drug for biological action, and the desired period of drug release.
The concentration of the active compound in the composition will also depend on the rate of absorption, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. Obviously, the dosage will also vary with the severity of the condition to be alleviated. It is further contemplated that specific dosages for any particular subject will be adjusted at any time according to the individual need and the professional judgment of the person administering or controlling the composition, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practical application of the claimed compositions. The composition may be administered at one time or may be divided into several smaller doses, administered at different time intervals.
The biologically active material is typically present in the composition in an amount of from about 0.5% to about 20% by weight, more typically from about 1% to about 15% by weight, or more, of the total weight of the composition. Still more preferably from about 2% to about 10% by weight of the total weight of the composition. Very active agents, such as growth factors, are preferably present at less than 1% by weight, and at less than 0.0001% by weight of the total composition.
Both soluble and insoluble materials can be dispersed in the HVLCM or LVLCM for controlled delivery.
Additives III
Various additives may optionally be added to the HVLCM or LVLCM to modify the properties of the material as desired. The additives may be present in any amount sufficient to provide the desired properties to the composition. The amount of additive used will generally vary with the nature of the additive and the effect to be achieved, and can be readily determined by the operator.
When present in the composition, the additive is typically present in an amount of about 0.1% to about 20% by weight of the total weight of the composition, more typically about 1,2 or 5% to about 10% by weight of the total weight of the composition. Certain additives, such as buffers, are present in the composition in only minor amounts.
The following categories are non-limiting categorical examples of additives that may be used in the composition. After understanding the present disclosure and achieving the objectives, one skilled in the art will readily understand how to select other additives to achieve the desired objectives. All of these embodiments are considered to be within the scope of the disclosed invention.
A. Biodegradable polymers
One class of additives are biodegradable polymers and oligomers. The polymer may be used to modify the release profile of the delivered agent, to increase the integrity of the composition, or to modify the properties of the composition. Non-limiting examples of suitable biodegradable polymers and oligomers include: poly (lactide), poly (lactide-co-glycolide), poly (caprolactone), polyamides, polyanhydrides, polyamino acids, polyorthoesters, polycyanoacrylates, poly (phosphazines), poly (phosphates), polyamide esters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, degradable polyurethanes, polyhydroxybutyrate, polyhydroxyvalerate, polyalkylene oxalate, polyalkylene succinate, poly (malic acid), chitosan, and copolymers, terpolymers, oxidized cellulose, compositions or mixtures thereof.
Examples of poly (a-hydroxy acids) include poly (glycolic acid), poly (DL-lactic acid), poly (L-lactic acid), and copolymers thereof. Examples of polylactones include poly (e-caprolactone), poly (d-valerolactone), and poly (γ -butyrolactone).
B. Non-biodegradable polymers
Another class of additives useful in the compositions of the present invention are non-biodegradable polymers. Non-limiting examples of non-degradable polymers that can be used as additives include: polyacrylates, ethylene vinyl acetate polymers, cellulose and cellulose derivatives, acyl substituted cellulose acetates and derivatives thereof, non-degradable polyurethanes, polystyrene, polyvinyl chloride, polyvinyl fluoride, polyvinyl imidazole), chlorosulfonated polyolefins, and polyethylene oxide.
Preferred non-biodegradable polymers include polyethylene, polyvinylpyrrolidone, ethylene vinyl acetate, polyethylene glycol, cellulose acetate butyrate ("CABO"), and cellulose acetate propionate ("CAP").
C. Oils and fats
Yet another class of additives useful in the compositions of the present invention are natural and synthetic oils and fats. Oils derived from animal or nut plant seeds typically include glycerides of fatty acids, primarily oleic, palmitic, stearic and linolenic acids. Generally, the more hydrogen the molecule contains, the more viscous the oil.
Non-limiting examples of suitable natural and synthetic oils include crude or refined vegetable oils, peanut oil, medium chain triglycerides, soybean oil, almond oil, olive oil, sesame oil, peanut oil, fennel oil, camellia oil, corn oil, castor oil, cottonseed oil, and soybean oil, and medium chain fatty acid triglycerides.
Fats are typically glycerides of higher fatty acids, such as stearic and palmitic acids. These esters and mixtures thereof are solid at room temperature and exhibit a crystalline structure. Lard and tallow are examples. In general, oils and fats increase the hydrophobicity of SAIB, slowing degradation and water absorption.
D. Carbohydrates and carbohydrate derivatives
Yet another class of additives useful in the compositions of the present invention are carbohydrates and carbohydrate derivatives. Non-limiting examples of such compounds include monosaccharides (monosaccharides), such as fructose and its isomer glucose (dextrose); disaccharides such as sucrose, maltose, cellobiose, and lactose; and a polysaccharide.
Solvent IV
When the composition is used as a LVLCM, it should contain a solvent that can dissolve the HVLCM. Preferably, the substance to be delivered is also soluble in the solvent. The solvent should be non-toxic, soluble or miscible with water, and biocompatible. Toxic solvents are not used in medicine or agriculture. The solvent used to inject the composition into the animal should not cause significant irritation or necrosis of the tissue at the injection site unless such irritation or necrosis is the desired effect.
The solvent should be at least water soluble so as to be capable of rapidly diffusing into body fluids or other aqueous media to coagulate or solidify the composition. Examples of suitable solvents include ethanol, ethyl lactate, propylene carbonate, hydrofurfuryl polyglycol ether (glycofurol), N-methylpyrrolidone, 2-pyrrolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, benzyl alcohol, triacetin, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethyl sulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one.
When SAIB is used as the HVLCM, preferred solvents are ethanol, dimethyl sulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate, and glycofurol. SAIB is not miscible with glycerol, corn oil, peanut oil, 1, 2-propanediol, polyethylene glycol (PEG200), ultra-refined sesame oil, and ultra-refined peanut oil. Thus, the latter group of solvents is not preferred for use with SAIB.
The amount of solvent added to the composition is generally from about 5% to about 55% by weight of the total weight of the composition. The solvent is preferably present in the composition in an amount of about 10% to about 50% by weight. And more preferably from about 10% to about 30% by weight.
Use of LVLCX and HVLCX compositions
The compositions of the present invention may be administered to a subject by a variety of methods, which may vary depending on the effect desired. For example, when the subject is an animal (e.g., human), the composition can be administered topically, systemically [ e.g., via the mucosa (oral, rectal, vaginal or nasal) or parenterally (intravenous, subcutaneous, intramuscular, intraperitoneal) ], with an appropriate carrier if necessary. When the composition is used in agriculture, it may be applied by an applicator such as a drench, spray dip, spray or spray.
For use in medicine or veterinary medicine, the compositions of the invention are preferably administered as a solution by injection, or in the form of an aerosol, ointment or emulsion. When administered by injection as a LVLCM, the small amount of solvent used in the composition is immersed in the aqueous fluid of the subject, thereby forming a high viscosity reservoir of the controlled delivery substance, or a protective layer of tissue that prevents or minimizes adhesions. When used in aerosol or emulsion form, a small amount of solvent in the solution will evaporate after application, thereby solidifying the LVLCM into the HVLCM. Aerosol and emulsion formulations may be prepared by methods familiar to those skilled in the art. See, e.g., Ansel, H.C (Ansel, H.C), et alPharmaceutical dosage forms and drug delivery systems(Pharmaceutical Dosage Forms and Drug Del’Systems)Sixth edition, 1995.
The compositions of the present invention are useful for forming a tissue protective layer, and are particularly useful for preventing the development of surgical adhesions. The HVLCM can adhere to surrounding tissue or bone and can therefore be injected subcutaneously like collagen to reinforce tissue or fill voids. The HVLCM can also be injected into wounds, including burn wounds, to prevent deep scarring. The degradation time of the HVLCM can be adjusted, for example, by using a polymer as an additive to the HVLCM. Thus, an implant formed by the HVLCM will slowly biodegrade in vivo, with normal tissue growing and displacing the implant as it disappears.
In another embodiment, the bioactive agent may be encapsulated in the microspheres prior to mixing into the composition of the present invention. In yet another embodiment, the biologically active substance may be complexed with a complexing agent, such as a cyclodextrin. In yet another embodiment, the biologically active substance is in the form of a prodrug.
Other methods of using the invention include orally administering a carrier or controlled release formulation in a gelatin capsule; encapsulating the carrier or controlled release formulation in microspheres or microcapsules, wherein the microspheres are preferably biodegradable polymers such as poly (DL-lactide-co-glycolide); and combining the carrier or controlled release formulation with inactive pharmaceutical excipients, such as microcrystalline cellulose or cellulose acetate, and then optionally forming the composition into a spherical or other shape and mixing into a dosage form.
Topical oral delivery of compositions
Topical oral delivery systems may be formulated according to the present invention, including surfactants, co-surfactants, oily components, HVLCM, such as sucrose acetate isobutyrate, and water to ensure delivery of the active agent to the oral cavity.
For example, the present invention may be used to formulate an emulsion-like extended-action mouthwash comprising SAIB and an active agent in an aqueous-based second carrier material. For example, if the mouthwash is used routinely before bedtime, it will reduce bad breath the next morning.
The components in the mouthwash preparation can be divided into six types: antimicrobial actives, surfactants, co-surfactants, oily components, sucrose acetate isobutyrate, water, and additives. Each of the above components will be described in detail below. With the knowledge of these disclosures, one of ordinary skill can formulate other topical, oral delivery systems for use in a wide range of fields, including the treatment of oral infections and other oral conditions, by selecting appropriate active agents.
Antimicrobial actives. Antimicrobial actives commonly used in mouthwash formulations may include, but are not limited to, domiphen bromide, triclosan, chlorhexidine, essential oils, cetyl pyridinium chloride, fluoride, biguanide, salicylanilide, zinc compounds, and antibiotics. These active agents may be used alone or in admixture. Cetyl pyridinium chloride and zinc compounds are preferred, and zinc gluconate is particularly preferred.
Surface active agent. The surfactants selected for use in the formulations of the present invention are typically water-soluble nonionic surfactants including, but not limited to, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene glycerides, and sorbitan fatty acid esters, which may be used alone or in admixture. Preferred nonionic surfactants are polyoxyethylene sorbitan fatty acid esters containing 5 to 40 moles of ethylene oxide and polyoxyethylene glycerides containing 5 to 20 moles of ethylene oxide. Polyoxyethylene (20E.O.) sorbitan monooleate, polyoxyethylene (20E.O.) almond oil, polyoxyethylene (20E.O.) hydrogenated castor oil, etc. are particularly preferred.
The amount of surfactant added to the formulations of the present invention will vary depending on the type of surfactant used. In general, it is preferably from 1 to 60% by weight, particularly preferably from 2 to 10% by weight.
Cosurfactant. The co-surfactant used in the formulations of the present invention is typically specified as an alcohol or as a low hydrophilic/lipophilic balance (HLB) nonionic component of the surfactant/co-surfactant system. In the formulations of the present invention, cosurfactants having the function of solubilizers or cosolvents are preferred in addition to the function of surfactants. Mono-or polyhydroxy alcohols or low HLB nonionic surfactants may be used alone or in combination of two or more as such cosurfactants. Specific benzyl alcohol, ethanol, octanol and the like are examples of monohydric alcohols; propylene glycol, glycerin, 1, 3-butylene glycol, and the like are examples of the polyhydric alcohol. Specific distilled monoglycerides, polyglycerol polyoleate and polyethylene glycols having a molecular weight of 300-. Specific polyglycerol polyoleates are more preferred examples of cosurfactants. A particularly preferred co-surfactant is decaglycerol tetraoleate.
The amount of the above-mentioned co-surfactant added to the formulation of the present invention varies depending on the type of co-surfactant used. In general, it is preferably from 0.5 to 30% by weight, particularly preferably from 1 to 5% by weight.
Oily component. One or more oily components generally selected from glycerin fatty acid esters, fatty alcohols and derivatives thereof, fatty alcohol benzoates, and hydrocarbons may be used as the oily component in the preparation of the present invention. Acceptable mono-, di-or triglycerides and mixtures thereof, whether they are derived or produced from natural or synthetic compounds, or semi-synthetic compounds, may be used as the glycerol fatty acid ester. Preferred glycerol fatty acid esters are crude or refined almond oil, olive oil, sesame oil, peanut oil, fennel oil, camellia oil, corn oil, castor oil, cottonseed oil, and soybean oil, and medium chain fatty acid triglycerides, which can be used alone or in admixture. Particularly preferred are medium chain fatty acid triglycerides.
Preferred fatsThe fatty acid ester is isopropyl myristate, octyl palmitate, ethyl oleate and ethyl palmitate. Isopropyl myristate and octyl palmitate are particularly preferred. Particularly preferred fatty alcohol derivatives and fatty alcohol benzoates are 2-octyldodecanol and C12-15Alcohol benzoates. Certain light or heavy liquid paraffin oils are preferred hydrocarbons.
The oily component can be used alone or in combination with other oily components. These oily components may be incorporated in the formulations of the invention in amounts of from 0.5 to 50% by weight, preferably from 1 to 10% by weight.
Sucrose acetate isobutyrate. Sucrose acetate isobutyrate, detailed above, was used as the HVLCM. SAIB is typically added to the formulation in an amount of 0.01 to 10% by weight, preferably 0.1 to 2% by weight.
Water (W). Another important component in mouthwash formulations is water. The pH of the formulation of the present invention is 3 to 10, preferably 5 to 9, more preferably 6 to 8, the pH can be maintained in the above range by using a buffer. Specific acetic acid, citric acid, phosphoric acid, benzoic acid and/or their salts are examples of preferred buffers. During the formulation, the pH can be adjusted to the preferred range by adding an appropriate acid or base (preferably hydrochloric acid or sodium hydroxide), as necessary for adjustment. It is also preferred that the water used in the formulation of the present invention is deionized and filtered.
Additive agent. Other components such as preservatives, stabilizers, antioxidants, pigments, isotonizing agents, flavoring agents, humectants, masking agents, vitamins and vitamin precursors and the like may be added as desired. Specific paraben derivatives are preferred examples of preservatives, with specific methyl paraben and propyl paraben being the most preferred preservatives. Specific butylhydroxyanisole, butylhydroxytoluene, propyl gallate, vitamin E acetate and purified hydroquinone are preferred examples of antioxidants, with specific vitamin E acetate and butylhydroxytoluene being the most preferred antioxidants. Specific sorbitol is a preferred example of a humectant. Specific peppermint oil, spearmint oil, wintergreen oil, menthol and mixtures thereofSaccharin is a preferred example of a flavoring agent. Specific citric acid is a preferred example of a masking agent.
The topical oral delivery system described above may be formulated by conventional methods, for example, by separately preparing an oil phase and an aqueous phase, and then mixing the oil and water phases at elevated temperatures. And fully mixing the oil-water two-phase mixture, cooling to room temperature, and packaging.
VI. examples
One of ordinary skill in the art, with knowledge of the present disclosure, will be able to formulate and use a variety of HVLCH compositions. It is intended that all such embodiments fall within the scope of the present invention. For ease of illustration, the following examples will detail the formulation and use of SAIB compositions. Other HVLCMS, additives, matrices, and solvents may be used in the same or similar manner.
The following general procedure was used to formulate the formulations required in the examples. The formulations were prepared in 20ml scintillation vials and then shaken, stirred and/or heated to dissolve the bioactive substance in the SAIB/solvent system. In the example where the biologically active substance is insoluble, the formulation is frozen and then stirred to form an optimal dispersion of the biologically active substance in the form of droplets.
In glass tubes, the release of the biologically active compound can be determined by the following general method. Phosphate buffered saline ("PBS") (10ml) at pH 7.4 or 6.8 was added to a 16X 125mm tube. The pH of PBS (7.4 or 6.8) is selected according to the use and solubility of the biologically active substance. The PBS contained 0.2% sodium azide to prevent microbial growth. To the above test tube 0.03-0.09 g of SAIB/solvent/biologically active substance formulation was added using a disposable plastic pipette and the weight was recorded. The tube was capped, placed in a shaker bath apparatus, and constantly shaken at 37 ℃.
The test tubes were removed from the shaker bath at different time timings. PBS was immediately removed from the tubes containing the formulation and placed into clean, dry tubes. These samples were subjected to UV analysis to determine the amount of bioactive substances in the PBS solution. Fresh PBS was added to the tube containing the formulation above, and the tube was returned to the shaker bath. The above steps are repeated at different sampling times.
The release profile is plotted from the concentration of the biologically active substance in the release solution, based on the original amount of biologically active substance in the formulation. The original amount of biologically active substance in the formulation was determined by UV-visible spectrophotometry.
Various solvents are employed in these examples, including: ethanol (EtOH), Dimethylsulfoxide (DMSO), ethyl lactate (EtLac), ethyl acetate (EtOAc), benzyl alcohol (FCH)2OH), triacetin, N-methylpyrrolidone (NMP), Propylene Carbonate (PC) and glycofurol (gf).
In formulations, a greater proportion of solvent will generally provide a higher concentration of biologically active substance. The amount and type of solvent is also directly related to the viscosity of the solution. Table 1 lists the effect of solvent and concentration on the SAIB/solvent mixture. The viscosity data was measured using a Cannon-Penske (Cannon-Penske) viscometer No. 200 at 30 ℃.
| TABLE 1 |
| Material | Centipoise (centipoise) |
| Reverse osmosis deionized water | 1.0 |
| EtOH | 1.3 |
| 60/40 SAIB/EtOH | 7.7 |
| 70/30 SAIB/EtOH | 17.0 |
| 55/40/5 SAIB/EtOH/CAB | 68.9 |
| 90/10 SAIB/EtOH | 494.8 |
| PC | 2.1 |
| 70/30 SAIB/PC | 138.7 |
| 70/30 SAIB/glycofurol | 228.4 |
| Peanut oil | 57.8 |
Influence of biologically active substances
Methylene blue and Bovine Serum Albumin (BSA) were used to illustrate the release of the drug. The bioactive compounds released from the system include chlorhexidine, diclofenac, doxycycline, flurbiprofen, naproxen, and theophylline. Clotrimazole is not released continuously due to its low water solubility.
Example 1
Ethanol (1g) was mixed with Sucrose Acetate Isobutyrate (SAIB) (9 g). After slow stirring a clear solution with low viscosity was obtained. A glass pipette is used to drop a drop of the solution into water to form a spherical matrix, the shape of which can be maintained for more than one week.
Example 2
Ethanol (2g) was mixed with SAIB (8 g). The resulting solution forms a film when mixed with water. The shape of the film can be maintained for more than one week.
Example 3
Solutions containing varying amounts of ethanol and SAIB were prepared according to the method of example 1. To this solution 0.07% methylene blue was added. Spherical droplets were made in Phosphate Buffered Saline (PBS) as described in example 1. PBS samples were stored at 37 ℃. PBS samples were taken at regular intervals and analyzed for methylene blue content by UV-visible spectrophotometry. The results of the release of methylene blue are shown in FIG. 1.
Example 4
A series of formulations were prepared according to example 3 using Bovine Serum Albumin (BSA) instead of methylene blue. Different percentages of BSA, solvent and SAIB were used in these formulations. The solvent indices and the proportions of BSA, solvent, SAIB and any additives are given in tables 2-4 below. The release of BSA slowed with increasing CAP: SAIB ratio.
BSA is insoluble in the above system. Attempts have been made to dissolve BSA in mixed solvents, but BSA only dissolves in glycerol and water which are not miscible with SAIB. All BSA-containing formulations were heterogeneous in the release profile. Table 2 lists BSA-containing formulations.
TABLE 2
| ％BSA | ％EtOH | ％PVP | % 50/50 Glycerol/DMSO |
| 27 | 37 | 0 | 4.4 |
| 4.6 | 36 | 0 | 5.6 |
| 5.5 | 36 | 0 | 5.8 |
| 5.0 | 33 | 5.9 | 6.9 |
| 5.5 | 31 | 8.2 | 8.3 |
| 4.9 | 27 | 18.8 | 9.8 |
TABLE 3
| ％BSA | Solvent(s) | % solvent | Additive agent | % additives |
| 1.1 | PC | 31.3 | Deionized water | 9.8 |
| 9.2 | Solvent-free (BSA/SAIB soft) pastes |
| 9.6 | Glycerol | 9.2 | - | - |
| 1.9 | EtOH | 30 | - | - |
| 1.9 | EtOH | 20 | - | - |
| 1.9 | EtOH | 10 | - | - |
| 10 | EtOH | 10 | - | - |
FIG. 5 illustrates the release profile of SAIB/BSA ointment formulated without any added solvent. Attempts have been made to plot the release profiles of the heterogeneous formulations listed in table 4, but have not been achieved.
TABLE 4
| ％BSA | Solvent(s) | % solvent | Additive agent | % additives |
| 1 | EtOH | 9.6 | - | - |
| 1 | EtOH | 19 | - | - |
| 1 | EtOH | 29 | - | - |
| 1 | EtOH | 50 | - | - |
| 1 | EtOH | 89 | - | - |
Example 5
The procedure of example 3 was repeated using a series of formulations containing chlorhexidine as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives.
The formulations with chlorhexidine as the bioactive substance are listed in table 7 below.
TABLE 5
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 5 | EtLac | 50 | - | - | Insoluble matter |
| | 30 | - | - | Insoluble matter |
| | 10 | - | - | Insoluble matter |
| NMP | 50 | - | - | Soluble in water |
| | 30 | - | - | Insoluble matter |
| | 10 | - | - | Insoluble matter |
| PC | 31 | - | - | Insoluble matter |
| | 20 | - | - | Insoluble matter |
| | 10 | - | - | Insoluble matter |
| EtOH | 50 | - | - | Soluble in water |
| | 30 | - | - | Insoluble matter |
| | 10 | - | - | Insoluble matter |
| | 45 | CAB | 5 | Soluble in water |
| | 40 | | | Soluble in water |
| | 35 | | | Insoluble matter |
| 2.6 | | 23 | PVP | 5.1 | Insoluble matter |
| 2.5 | | 23 | CAB | 5 | Insoluble matter |
| | 23 | CAP | 5 | Insoluble matter |
| 2.75 | | 23 | PEG(10K) | 5.2 | Insoluble matter |
| 2.4 | | 23 | PEG(1K) | 5.5 | Insoluble matter |
The release profiles of chlorhexidine in various solvents are shown in figures 6-8.
The optimal dissolving amount of the chlorhexidine in the SAIB/EtOH/CAB is deduced. The results are shown in Table 6.
TABLE 6
| % of the drugs | ％EtOH | ％CAB | Solubility in water |
| 12 | 57.5 | 3 | Insoluble at room temperature (soluble by heating) |
| 14.7 | 47.2 | 3.8 | Can be dissolved in one or two days |
| 15 | 51 | 3.4 | Insoluble matter |
| 18 | 50.4 | 3.1 | Insoluble matter |
Example 6
The procedure of example 3 was repeated using a series of formulations containing sodium diclofenac as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives. The release of diclofenac slows down with increasing CAB to SAIB ratio.
The formulations with diclofenac as bioactive substance are listed in table 7 below.
TABLE 7
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 2.68 | EtOH | 19.1 | - | - | Insoluble matter |
| 2.48 | | 15.6 | - | - | Insoluble matter |
| 2.40 | | 9.6 | - | - | Insoluble matter |
| 2.68 | | 7 | - | - | Insoluble matter |
| 2.43 | | 7.1 | Sucrose | 2.6 | Insoluble matter |
| 2.56 | | 3.6 | Sucrose | 5.1 | Insoluble matter |
| 2.39 | | 28.7 | CAB | 4.8 | Soluble in water |
| 2.44 | | 28.6 | PEG(1K) | 4.8 | Insoluble matter |
| 2.89 | | 28.7 | PVP(25) | 4.8 | Insoluble matter |
| 2.38 | | 28.3 | PEG(10K) | 5.3 | Insoluble matter |
| 2.35 | | 36.3 | CAP | 5.2 | Soluble in water |
| 2.57 | Glycerol triacetate | 50 | - | - | Insoluble matter |
| 2.89 | | 30 | - | - | Insoluble matter |
| 2.43 | | 11.5 | - | - | Insoluble matter |
| 2.58 | DMSO | 50 | - | - | Soluble (but brownish) |
| 2.45 | | 30.5 | - | - | Insoluble matter |
| 2.36 | | 10.2 | - | - | Insoluble matter |
The release profiles of diclofenac in various solvents are shown in figures 9-12.
Example 7
The procedure of example 3 was repeated using a series of formulations containing doxycycline as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives.
The formulations with doxycycline as the bioactive substance are listed in table 8 below.
TABLE 8
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 5 | EtOH | 15 | - | - | Insoluble matter |
| 2.56 | | 15 | - | - | Insoluble matter |
| 4.97 | EtOAc | 30 | - | - | Insoluble matter |
| 2.5 | EtLac | 30 | - | - | Insoluble matter |
| 2.45 | PC | 30 | - | - | Insoluble matter |
| 2.5 | GE | 30 | - | - | Soluble in water |
| 2.5 | DMSO | 30 | - | - | Temporary insolubility |
A small amount of DMSO was used with the SAIB/EtOH/CAB composition to aid in doxycycline dissolution. These formulations are listed in table 9 below.
TABLE 9
| % doxycycline | ％EtOH | ％CAB | ％DMSO | Solubility in water |
| 3.01 | 49 | 6.7 | 7.6 | Soluble in water |
| 4.03 | 47 | 8.9 | 7.9 | Soluble in water |
| 3.07 | 42 | 5.6 | 7.4 | Insoluble matter |
| 4.17 | 72 | 21 | 7.5 | Soluble (note: no SAIB) |
Example 8
The procedure of example 3 was repeated using a series of formulations containing flurbiprofen as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives.
The formulations with flurbiprofen added as the bioactive substance are listed in table 10 below.
Watch 10
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 2.48 | EtOH | 15 | - | - | Soluble in water |
| 4.98 | EtOH | 15 | - | - | Soluble in water |
| 9.98 | EtOH | 15 | - | - | Soluble in water |
| 4.99 | EtOH | 45 | CAB | 5.0 | Soluble in water |
| 9.92 | EtOH | 45 | CAB | 5.5 | Soluble in water |
The release profile of flurbiprofen is shown in figure 13.
Example 9
The procedure of example 3 was repeated using a series of formulations containing naproxen (free acid) as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives.
Formulations with naproxen (free acid) as the bioactive substance are listed in table 11 below.
TABLE 11
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 5.2 | GF | 21 | - | - | Soluble in water |
| 3.6 | GF | 37 | - | - | Soluble in water |
| 4.1 | GF | 44 | - | - | Soluble in water |
Example 10
The procedure of example 3 was repeated using a series of formulations containing naproxen (sodium salt) as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives.
Naproxen (sodium salt) was insoluble in ETOH and EtOAc. The formulations with naproxen (sodium salt) added as the biologically active substance are listed in table 12 below.
TABLE 12
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 5.2 | GF | 21 | - | - | Insoluble matter |
| 3.4 | GF | 37 | - | - | Soluble in water |
| 3.9 | GF | 44 | - | - | Soluble in water |
The release profiles of naproxen (free acid and sodium salt) in various solvents are shown in figure 14.
Example 11
The procedure of example 3 was repeated using a series of formulations containing naproxen (sodium salt) and naproxen (free acid) as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives.
Formulations with naproxen (sodium salt) and naproxen (free acid) as the bioactive substances are listed in table 13 below.
Watch 13
| % free acid | % Na salt | Solvent(s) | % solvent | Solubility in water |
| 2.38 | 2.55 | PC | 20 | Insoluble matter |
| 1.28 | 3.56 | GF | 20 | Insoluble matter |
| 2.27 | 2.78 | EtLac | 30 | Soluble in water |
| 2.49 | 2.55 | GF | 20 | Soluble in water |
Example 12
The procedure of example 3 was repeated using a series of formulations containing theophylline as the bioactive agent. Formulations were formulated containing varying amounts of solvent, SAIB and additives.
The formulations with theophylline as the bioactive substance added are listed in table 14 below.
TABLE 14
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 0.5 | EtOH | 15 | - | - | Insoluble matter |
| 1 | EtOH | 15 | - | - | Insoluble matter |
| 2.5 | EtOH | 15 | - | - | Insoluble matter |
| 5 | EtOH | 15 | - | - | Insoluble matter |
| 10 | EtOH | 15 | CAB | 5 | Insoluble matter |
| 2.5 | EtOH | 53 | CAB | 10 | Insoluble matter |
| 2.5 | EtOH | 47 | CAB | 15 | Insoluble matter |
| 2.5 | EtOH | 43 | CAP | 5 | Insoluble matter |
| 2.5 | EtOH | 53 | CAP | 10 | Insoluble matter |
| 2.6 | EtOH | 48 | CAP | 15 | Insoluble matter |
| 2.5 | EtOH | 43 | - | - | Insoluble matter |
| 5.2 | EtOAc | 48 | - | - | Insoluble matter |
| 4.8 | EtOAc | 29 | - | - | Insoluble matter |
| 5.0 | EtOAc | 9.5 | - | - | Insoluble matter |
| 5.0 | FCH2OH | 48 | - | - | Insoluble matter |
| 5.2 | FCH2OH | 29 | - | - | Insoluble matter |
| 5.0 | FCH2OH | 11 | - | - | Insoluble matter |
| 5.4 | EtOH | 10 | - | - | Insoluble matter |
| 6.5 | EtOH | 20 | - | - | Insoluble matter |
| 5.5 | EtOH | 30 | - | - | Insoluble matter |
| 5.5 | EtOH | 25 | CAB | 5.5 | Insoluble matter |
| 7.2 | EtOH | 34 | CAB | 5.4 | Insoluble matter |
| 5.4 | EtOH | 45 | CAB | 5.9 | Insoluble matter |
| 5.1 | PC | 11 | - | - | Insoluble matter |
| 5.5 | PC | 20 | - | - | Insoluble matter |
| 5.5 | PC | 31 | - | - | Insoluble matter |
The release profile of theophylline from propylene carbonate is shown in figure 16.
Attempts were made to plot the release profile of the following theophylline-containing formulation, but the sample was very turbid.
The amounts of materials in these formulations are listed in table 15 below.
Watch 15
| % of the drugs | Solvent(s) | % solvent | Additive agent | % additives | Solubility in water |
| 4.9 | EtOH | 16 | PVP(K25) | 5.1 | Insoluble matter |
| 5.0 | EtOH | 40 | PVP(K25) | 5.0 | Insoluble matter |
| 5.1 | EtOH | 15 | PEG(1K) | 5.0 | Insoluble matter |
| 5.0 | EtOH | 40 | PEG(1K) | 5.0 | Insoluble matter |
| 4.9 | EtOH | 40 | PEG(10K) | 5.4 | Insoluble matter |
| 4.9 | EtOH | 16 | PEG(10K) | 4.9 | Insoluble matter |
Example 13
Formulations containing 80% SAIB and 15% ethanol were prepared and the resulting solutions were filled into aerosol containers. The solution was sprayed onto a flat surface of agar medium to form an adherent continuous film thereon.
Example 14
A series of formulations containing 80% SAIB, 0.02% methylene blue and varying ratios of ethanol/CAB (1: 0-1: 1) were prepared. The formulation was sprayed onto gelatin and penetration of methylene blue into gelatin slowed with increasing CAB content.
Example 15
SAIB was heated to 60 ℃. Various formulations were formulated containing 1,2, 5 and 10% tetracycline. The formulation was loaded into a syringe with a 21 gauge needle. The formulation was pushed by hand from the syringe into the buffer at 37 ℃. The formulation is easily pushed out at about 45 ℃.
Example 16Preparation and performance of gargle
Polyoxyethylene (7.680g, 20E.C.) almond oil (Crovol a-70), 4.042g decaglycerol tetraoleate (Caprol 1OG40) and 11.721g medium chain triglycerides (Neobee M-5) were mixed in a suitable mixer (jacketed one-way inclined kettle). The mixture was heated to about 65 ℃. Methyl paraben (0.500g), 0.250g propyl paraben, 0.125g cetylpyridinium chloride, 0.125g benzoic acid and 0.625g sucrose acetate isobutyrate were mixed into the heated organic phase. The organic phase mixture was maintained at about 65 ℃ throughout the addition of the above components. Zinc gluconate (0.250g), 0.125g sodium benzoate, 0.0625g citric acid and 12.5g sorbitol were dissolved in 221.10g deionized water. The aqueous mixture was heated to about 65 ℃. After both the organic phase mixture and the aqueous phase mixture reached temperature, the aqueous phase was slowly added to the oil phase with stirring. After the water phase was completely added to the oil phase, two drops of green food color and 1.000g peppermint oil were added and mixed well into the formulation. The mixture was rapidly cooled to room temperature and then packaged. During the formulation at the above scale, the water loss was about 10.1 g.
The composition of the finished product is as follows.
TABLE 16
| Mouthwash composition | Concentration%, by weight |
| PEG-20 Almond oil | 3.07 |
| Medium chain triglycerides | 4.70 |
| Decaglycerol tetraoleate | 1.62 |
| Water (W) | 84.4 |
| Sucrose acetate isobutyrate | 0.250 |
| Mint oil | 0.400 |
| P-hydroxybenzoic acid methyl ester | 0.200 |
| Propyl p-hydroxybenzoate | 0.100 |
| Cetyl pyridine chloride | 0.050 |
| Zinc gluconate | 0.100 |
| Saccharin | 0.020 |
| Sorbitol | 5.00 |
| Sodium benzoate | 0.050 |
| Citric acid | 0.025 |
| Benzoic acid | 0.050 |
| Green edible pigment | According to the requirements |
Example 17
The transplanted vessels were soaked in a solution of 61.8% SAIB, 10.0% CAB and 28.2% ETOH to which 1% heparin was added. The solution in the graft vessel was squeezed out and washed with physiological saline. The graft vessel was implanted into dogs. After grafting, the inner surface of the graft vessel was free of blood clots, as compared to the control graft vessel.
Example 18
Formulations of 5% CAB, 45% ethanol and 50% SAIB were prepared. 0.05-0.0005% of transforming growth factor-beta or 1-5.1% of phenol is added to the preparation. The composition is injected into the groin of the dog, where it induces a cellulase response, resulting in groin closure.
Example 19b
A formulation of 10% CAB, 45% ethanol and 45% SAIB was sprayed as an aerosol onto the uterine horn of surgically abraded rabbits. At review, the site showed no surgical adhesions at all but the formulation was fully physiologically tolerable.
Example 20
Figure 17 is a release profile of two formulations. One formulation (dark shading) contained 3.2% SAIB, 15.1% ETOH, 0.00395% methylene blue, and the remainder deionized water. Another formulation (shading) contained 0% SAIB, 28.9% ETOH, 0.00395% methylene blue, and deionized water.
A1-inch strip of native collagen was cut, rinsed with PBS (pH6.8), soaked in the above formulation for 9 minutes, and then placed in a clean tube and submerged in PBS. Gently pouring out PBS at different times for UV-analysis; fresh PBS was added to the collagen-containing tubes described above. See fig. 17.
Variations and modifications of the present invention, compositions of the invention and methods of using the same will be apparent to those skilled in the art from the foregoing detailed description. It is intended that such changes and modifications be within the scope of the appended claims.