Background
The disclosures and other materials used herein to illuminate the background of the invention, and in particular cases to provide additional details respecting the practice, are incorporated by reference.
Bleeding disorders are one of the most common gynecological problems. The etiology of bleeding disorders and, in particular, the frequency of bleeding disorders varies depending on the age of the affected woman. During pre-and peri-menopausal periods, the most common diseases are due to hormonal as well as organic changes in the uterus, such as myomas, endometriosis or endometrial polyps. Without other identifiable causes, clotting defects lead to increased bleeding, especially in young and young women.
Dysfunctional uterine bleeding can be treated surgically or pharmaceutically. Surgical treatments include first and second generation endometriectomies and hysterectomies. Medication that avoids potentially unnecessary surgery is generally the only treatment of choice for treating excessive bleeding and for patients who wish to preserve reproductive function.
Despite the availability of many drugs, there is generally a lack of evidence-based approaches, significant differences in practice, and continuing uncertainty as to the most appropriate therapy. Adverse reactions and problems with compliance also impair the success of drug therapy.
Therapeutic drugs administered primarily orally consist of compounds that reduce menstrual bleeding, such as antifibrinolytic agents, nonsteroidal anti-inflammatory drugs, prostaglandin synthesis inhibitors, progestins, estrogen-progestin combinations (e.g., oral contraceptives), danazol (danazol), or gonadotropin-releasing hormone analogs.
Plasminogen activators are a group of enzymes that cause fibrinolysis (clot lysis). It has been found that women with heavy menstrual bleeding have an increased content of plasminogen activator in the endometrium compared to women with normal menstrual blood loss. Plasminogen activator inhibitors (i.e., anti-fibrinolytic agents and in particular tranexamic acid) have therefore been used to treat massive menstrual bleeding (see, e.g., Tauber et al, Am J Obstet Gynecol.1981, 6/1, 140 (3): 322-8; Wellington et al, drugs.2003, 63 (13): 1417-33; Lethaby et al, Cochrane DatabaseSyst. Rev.2000, (4): CD 000249; Bogers et al, Maturitas.2004, 3/15, 47 (3): 159-74). Prescription of tranexamic acid at the high oral doses required for the development is hampered due to possible side effects of the drug, such as an increased risk of forming blood clotting diseases (deep venous embolism). Anti-fibrinolytic therapy appears to cause a large reduction in objective measures of heavy menstrual bleeding, but is not associated with an increase in side effects when compared to placebo or other drug therapies (NSAIDs, oral luteal progestogens and etamsylate).
Danazol is a synthetic steroid with antiestrogenic and antiprogestinic activity and weak androgenic properties. Danazol inhibits estrogen receptors and progesterone receptors in the endometrium, resulting in endometrial atrophy (thinning of the inner wall of the uterus) and reduced menstrual blood loss and amenorrhea in some women. Compared to other drug treatments, danazol appears to be an effective therapeutic for massive menstrual bleeding, but it is uncertain whether a woman is acceptable (see, e.g., Robins, Curr women Health Rep.2001, 12 months, 1 (3): 196-. Oral use of danazol may be limited by its side effect profile, its acceptability to women, and the need for continued treatment. Treatment with danazol resulted in shorter duration of the menstrual period and more adverse events compared to NSAIDs, but this did not appear to affect the acceptability of the treatment.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have proven useful for the treatment of menorrhagia. NSAIDs reduce elevated prostaglandin levels in women with excessive menstrual bleeding and may also have beneficial effects on dysmenorrhea and headache pain (see, e.g., Lethaby et al, Cochrane Database Syst Rev.2002, (1): CD 000400). Furthermore, it is only taken during menstruation and is relatively cheap. Overall, NSAIDs have been shown to be less effective than tranexamic acid or danazol.
In addition to contraceptive effects, the combination of oral contraceptive pills also results in a substantial reduction in blood loss. Birth control pills contain synthetic forms of estrogen and progesterone which prevent ovulation and thereby reduce endometrial accumulation or thickening. Thus, most oral contraceptive users have a minor or minimal menstrual bleeding. Several synthetic progestagens balance the effects of estrogen normally produced by the body and reduce endometrial growth. Luteinizing Hormone Releasing Hormone (LHRH) and gonadotropin releasing hormone (GnRH) or analogues thereof also appear to reduce menstrual blood loss (see, e.g., Higham, Br J Hosp Med.1991, month 1, 45 (1): 19-21).
Some efforts have been made to treat irregular gynecological bleeding by using local administration, such as intrauterine implants and intrauterine devices.
European patents EP 24779 and EP 24781 relate to the use of amidine derivatives or amidine mixtures in combination with intrauterine devices at rates of 50 to 200 micrograms/day to produce an anti-proteolytic, anti-fibrinolytic and contraceptive effect.
International patent application WO 2006028431 relates to an intrauterine implant and a method for causing fibrosis and causing amenorrhea. In particular, the device refers to an implantable intrauterine implant that easily and consistently reduces or eliminates abnormal intrauterine bleeding. In addition, the device also serves as a uterine marker for observing endometrial tissue thickness and potential changes. The methods of the invention relate to methods of treatment and additional contraceptive effects.
International patent application WO 98/14169 relates to methods and compounds for treating abnormal uterine bleeding by using compounds that block the response of uterine stromal cells to angiogenic factors by interfering with growth factors themselves or by inhibiting or blocking receptors for those growth factors in uterine epithelial or stromal cells. The compound that blocks the response is introduced into the patient either systemically or locally into the uterus, for example via a drug-loaded intrauterine contraceptive device. However, the present application does not describe any practical embodiment for introducing compounds using such intrauterine devices.
Finally, the levonorgestrel intrauterine release system (levonorgestrel-releasementintrauterine system, LNG-IUS, such as MIRENA, developed by Bayer Schering Pharma Oy (Turku, Finland) has been shown to be as effective in treating large amounts of menstrual blood loss as such (see, e.g., Luukkanen et al, Contraception.1995 at 11 months, 52 (5): 269-76; Andersson et al, Br J Obstettgynacol.1990 at 8 months, 97 (8): 690-4; Moller et al, Hum Reprod.2005 at 5 months, 20 (5): 1410-7; Lethaby et al, Cochrane Database Rest v.2005 at 10 days 00219, (4): CD 126; and Cochrane Database Rest.2): 002126). LNG-IUS is a systemic hormonal contraceptive that provides an effective method of contraception and is fully reversible and has excellent tolerability profiles. The low dose of levonorgestrel released by this system ensures that hormone-related systemic adverse effects, which decrease gradually after the initial months of use, are minimized. It also provides non-contraceptive health benefits to the user. The local release of levonorgestrel within the endometrial cavity strongly inhibits endometrial growth because the endometrium becomes insensitive to ovarian estradiol. Endometrial suppression is responsible for reducing the duration and amount of menstrual bleeding and alleviating dysmenorrhea. By reducing menstrual blood loss, LNG-IUS increases iron accumulation in the body and thus may be used to effectively treat menorrhagia. In many women with menorrhagia, the use of these IUS may replace more invasive surgical procedures, such as hysterectomy or endometriectomy.
During the first months of IUS use, irregularities in vaginal bleeding patterns are the most common clinical side effects. These irregularities may include increased menstrual blood loss during the circulatory period, increased duration of bleeding during the period, and intermenstrual and punctate bleeding. The pathogenesis of bleeding disorders in IUS users is multifactorial and has been proposed to be of different etiology for different types of bleeding disorders. The local increase in fibrinolytic activity is the most recognized cause of increased menstrual blood loss. The deformation of the endometrial vasculature due to the presence of the intrauterine system can be explained by the direct action of the device on the superficial blood vessels, which leads to abrasions and erosions, possibly accompanied by irregular bleeding; and/or pressure deformation of the device, which may be transmitted through endometrial tissue and result in endothelial damage in functional areas of the endometrium with vulnerable and dysfunctional vascularization. Vascular injury will result in interstitial bleeding with the release of blood into the uterine cavity in an irregular pattern.
Not only does a large number of users of the levonorgestrel intrauterine release system (LNG-IUS) desire contraceptive protection, but also fewer menstrual problems. For LNG-IUS there is inappropriate bleeding, especially in the first 6 to 7 cycles after insertion. Complete amenorrhea is achieved by only a fraction of users even after prolonged use, and users often report occasional bleeding (i.e., irregular and unpredictable). In users, irregular bleeding is a common initial condition, and chronic bleeding is often the cause of discontinuation of use of the system. Accordingly, there remains a need for an intrauterine delivery system that uses an improved and safe method that will provide contraception and inhibit abnormal and/or irregular bleeding and achieve rapid induction of amenorrhea.
Detailed Description
The object of the present invention is to provide a method for contraception and for preventing or inhibiting abnormal and/or irregular endometrial bleeding and for achieving a rapid induction of amenorrhea by using an intrauterine delivery system comprising a progestogen or a drug having a progestogenic activity for a prolonged period of time and controlled release of the progestogen at a level required for contraception and a sufficient amount of one or more therapeutically active substances capable of inhibiting abnormal and/or irregular endometrial bleeding.
According to a specific embodiment of the invention, the intrauterine delivery system comprises a body construction and at least one reservoir comprising a core and optionally a membrane encasing the core, the core and the membrane essentially consisting of the same or different polymer compositions, wherein at least one reservoir comprises a progestogen or a drug having a progestogenic activity and at least one reservoir comprises a therapeutically active substance capable of suppressing abnormal and/or irregular endometrial bleeding. The intrauterine delivery system has a simple design and can be prepared by economically attractive manufacturing methods.
According to another embodiment, the intrauterine delivery system consists of a body construction and a reservoir comprising a core and optionally a membrane encasing the core, the core and the membrane essentially consisting of the same or different polymer compositions, wherein the reservoir comprises a progestogen or a drug having a progestogenic activity and a therapeutically active substance capable of suppressing abnormal and/or irregular endometrial bleeding.
According to another embodiment, the intrauterine delivery system consists of a body construction and at least two reservoirs comprising a core and optionally a membrane encasing the core, the core and the membrane essentially consisting of the same or different polymer compositions, wherein one reservoir comprises a progestogen or a drug having a progestogenic activity and the other reservoir comprises a therapeutically active substance capable of suppressing abnormal and/or irregular endometrial bleeding.
The core essentially comprises a polymeric composition, i.e., the core is a polymeric matrix in which the therapeutically active substance is dispersed. The polymer composition is selected according to the desired release rate. The release rate can be controlled by the film or by the film and the core, but the release rate can also be controlled by the core alone. Thus, even in the absence of a membrane or when the membrane which primarily regulates the release of the therapeutically active substance is damaged, the substance is not released in a completely uncontrolled manner and thus does not have side effects on the patient.
The polymer composition of the core and/or the membrane may be selected such that the intrauterine system releases a sufficiently predetermined amount of a progestogen or a compound having progestogenic activity and a therapeutically active substance capable of inhibiting and/or preventing abnormal and/or irregular endometrial bleeding. By using the intrauterine system according to the invention it is even possible to deliver a sufficient daily amount of a water soluble substance, such as tranexamic acid, which has not been shown to be possible by using the intrauterine systems of the prior art.
According to a specific example where the delivery system consists of two or more reservoirs, the reservoirs may be independently disposed on the body of the intrauterine system. They may also be arranged one within the other or one on the other, in which case they may be next to one another or may be separated from one another by a separating membrane or by an inert placebo compartment.
According to a specific example in which the at least two therapeutically active substances are in the same reservoir, the substances may be homogeneously mixed into the core material. The core may also comprise more than one segment or portion, e.g. 2, 3, 4 or 5 segments or portions, consisting of the same or different polymer compositions. At least one of these segments comprises a progestogen or a drug having progestogenic activity or one or more therapeutically active substances capable of inhibiting abnormal and/or irregular endometrial bleeding.
One or more of the segments may be an inert separator membrane or a placebo segment without any therapeutically active substance.
The advantage of using a separating membrane or inert placebo zone to separate the reservoir or core zones from each other is that the release rate is easier to control, since there is no or only minimal interaction between the active substances. The material and thickness of the separating membrane or placebo segment depend on the ability of the material to prevent penetration of the active substance. Most desirably, the separation membrane or placebo segment completely prevents mixing of the active substances that might otherwise disrupt the release pattern. Any combination of structures is naturally possible and within the scope of the invention.
The film may cover the entire reservoir or only a portion of the system (e.g., a section of the core), whereby the degree of extension may vary depending on a number of factors, such as the choice of materials and the choice of active materials. The polymer composition used for the film is a polymer composition that allows the release of the therapeutically active agent at a predetermined and constant release rate. The film thickness depends on the material and active substance used and the desired release profile, but is generally less than the thickness of the core member.
The film may be composed of more than one layer. Each layer has a thickness, and the thicknesses of the layers may be the same or different. The combination of film layers of different thickness or material or both provides further possibilities for controlling the release rate of the active agent.
The polymer compositions (i.e., of the core, the film, and the separation membrane or inert placebo zone, if present) may be the same or different and may represent one single polymer, or the polymer composition may consist of two or more polymers.
In principle, any polymer, biodegradable or non-biodegradable, can be used as long as it is biocompatible. As is known in the art, the release kinetics of a therapeutically active agent from a polymer-based delivery system depends on the molecular weight, solubility, diffusivity, and charge of the therapeutically active agent as well as the characteristics of the polymer, the loading percentage of the therapeutically active agent, the distance the therapeutically active agent must diffuse through the body of the device to reach the surface of the device, and the characteristics of any matrix or film.
Polysiloxanes, in particular poly (dimethylsiloxane) (PDMS), are very suitable as membranes or matrices for modulating the permeation rate of drugs. Polysiloxanes are physiologically inert and numerous therapeutically active substances are able to penetrate polysiloxane films, which also have the desired strength properties. The permeation rate of the therapeutically active substance can be adjusted to a desired level by modifying the polymeric material in a suitable manner, for example by adjusting the hydrophilic or hydrophobic properties of the material. For example, it is known from the literature that the addition of poly (ethylene oxide) groups or trifluoropropyl groups to PDMS polymers alters the permeation rate of therapeutically active substances.
Other examples of suitable materials include (but are not limited to): copolymers of dimethylsiloxane and methylvinylsiloxane, ethylene/vinyl acetate copolymers (EVA), polyethylene, polypropylene, ethylene/propylene copolymers, acrylic polymers, ethylene/ethyl acrylate copolymers, Polytetrafluoroethylene (PTFE), polyurethanes, thermoplastic polyurethanes and polyurethane elastomers, polybutadiene, polyisoprene, poly (methacrylate), polymethylmethacrylate, styrene-butadiene-styrene block copolymer, poly (hydroxyethyl methacrylate) (pHEMA), polyvinylchloride, polyvinylacetate, polyethers, polyacrylonitrile, polyethylene glycol, polymethylpentene, polybutadiene, polyhydroxyalkanoates, poly (lactic acid), poly (glycolic acid), polyanhydrides, polyorthoesters, hydrophilic polymers (such as hydrophilic hydrogels), polyethylene, polypropylene, polyethylene/propylene copolymers, poly (ethylene/propylene) copolymers, poly (ethylene/ethyl acrylate) copolymers, poly (tetrafluoroethylene) copolymers, poly (isoprene), poly (methacrylate), poly (methyl methacrylate), poly (styrene-butadiene-styrene block copolymers, poly (hydroxyethyl methacrylate) (pHEMA), poly (vinyl chloride), poly (, Crosslinked polyvinyl alcohol, neoprene, butyl rubber, room temperature-hardening hydroxyl-terminated organopolysiloxanes which harden to elastomers at room temperature after addition of a crosslinking agent in the presence of a curing catalyst, one-or two-component dimethylpolysiloxanes compositions which cure by hydrosilylation at room temperature or at elevated temperature, and mixtures thereof. It is also obvious to the expert in the field that suitable materials can consist of copolymers of the homopolymers mentioned above.
The structural integrity of the material may be enhanced by the addition of particulate materials such as silica or diatomaceous earth. The elastomer may also be mixed with other additives to adjust the hydrophilic or hydrophobic nature of the elastomer, taking into account that all additives need to be biocompatible and harmless to the patient. The core or membrane may also comprise other materials to further adjust the release rate of one or several therapeutic substances, for example comprising a complex forming agent, such as a cyclodextrin derivative, to adjust the initial burst of the substance to an acceptable or desired degree. Auxiliary substances, such as surfactants (tensides), defoamers, solubilizers or absorption retarders or mixtures of any two or more of these substances, may also be added to impart desired physical properties to the body of the delivery system.
According to a particular example, the core and the film consist of a silicone-based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer.
The term "elastomeric composition" may refer to a single elastomer, the deformation of which by strain is reversible such that the shape of the elastomer returns to some extent after strain. The elastomer composition may also be composed of two or more elastomers mixed with each other.
The term "silicone-based elastomer" is understood to encompass elastomers composed of poly (disubstituted siloxanes) in which the substituents are predominantly lower alkyl groups, preferably alkyl groups having from 1 to 6 carbon atoms, or phenyl groups, wherein the alkyl or phenyl groups may be substituted or unsubstituted. A widely used and preferred such polymer is poly (dimethylsiloxane) (PDMS).
The elastomeric composition may be selected from the group consisting of:
-an elastomeric composition comprising poly (dimethylsiloxane) (PDMS),
-an elastomer composition comprising a silicone-based elastomer comprising 3, 3, 3-trifluoropropyl groups attached to the silicon atoms of the siloxane units,
elastomer compositions comprising poly (alkylene oxide) groups in the form of alkoxy-terminated grafts or blocks linked to polysiloxane units via silicon-carbon bonds, or mixtures of these forms, and
-a combination of at least two thereof.
According to a preferred embodiment of the present invention, in the silicone-based elastomer, 1% to about 50% of the substituents attached to the silicon atoms of the siloxane units are 3, 3, 3-trifluoropropyl groups. The percentage of 3, 3, 3-trifluoropropyl substituents may be, for example, 5% -40%, 10% -35%, 1% -29%, or 15% -49.5%. The term "about 50%" means that the degree of 3, 3, 3-trifluoropropyl substitution is actually slightly less than 50%, since the polymer must contain a certain amount (about 0.15% of the substituent) of crosslinkable groups, such as vinyl groups or vinyl end-capping groups.
According to another preferred embodiment of the invention, the silicone-based elastomer comprises poly (alkylene oxide) groups, such that the poly (alkylene oxide) groups are in the elastomer in the form of alkoxy-terminated grafts or blocks of polysiloxane units, which grafts or blocks are linked to the polysiloxane units by silicon-carbon bonds. The poly (alkylene oxide) groups mentioned above are preferably poly (ethylene oxide) (PEO) groups.
Processes for preparing suitable polymers are given, for example, in International patent applications WO 00/00550, WO00/29464 and WO 99/10412 (all assigned to Leiras Oy).
Therapeutically active agents
The progestogen can be any therapeutically active substance having progestogenic activity sufficient to effect contraception. In another embodiment, the progestogenic compound is a steroidal progestogenic compound. Examples of suitable progestogenic compounds include the following: such as progesterone and its derivatives, cyclopropenones acetate (cyclopropenates), desogestrel (desogestrel), etonogestrel (etonogestrel), levonorgestrel, lineestrol (lynestrenol), medroxyprogesterone acetate (medroxyprogesterone acetate), norethisterone (norethisterone), norethisterone acetate (norethisterone acetate), norgestimate (norgestimate), drospirenone (drospirenone), gestodene (gestodene), 19-nor-17-hydroxypregenone ester, 17 α -ethynylsterone (17 α -acetylestrosterone) and its derivatives, 17 α -ethynyl-19-nor-sterone and its derivatives, norethindrone diacetate (norethindrone), dygestrel (dygesterone), hydroxynorethindrone (norethindrone), gestrel (norethindrone), and norethindrone (medroxystrel), and norethindrone (medroxystrel).
In a particular embodiment, the progestogenic compound is levonorgestrel. Other progestogens having significant angiogenesis inhibiting characteristics compared to levonorgestrel may be used in combination with the above mentioned drugs.
Without limiting the scope of the invention, therapeutically active substances that can be used in combination with the present invention to prevent or inhibit endometrial bleeding can be selected from the group consisting of: prostaglandin synthesis inhibitors, such as diclofenac sodium (diclofenac sodium); NSAIDs such as naproxen (naproxen), indomethacin (indomethacin), ibuprofen (ibuprofen), mefenamic acid (mefenamic acid), flurbiprofen (flurbiprofen); leukotriene inhibitors such as zafirlukast (zafirlukast) and montelukast (montelukast) and salts thereof; oxytocin (oxytocin) antagonists; trypsin inhibitors such as cisylol; a COX inhibitor; antifibrinolytics such as tranexamic acid and its precursors, aminocaproic acid, PAI-1, desmopressin (desmopressin), clomiphene citrate (clomiphene citrate), p-aminomethyl-benzoic acid; an estrogen; an antiestrogen; an aromatase inhibitor; an interleukin inhibitor; a glucocorticoid; a progestin with significant glucocorticoid activity; danazol; and gestrinone (gestrinone).
The above mentioned drugs have been used to some extent for systemic treatment of menorrhagia. Furthermore, it is also possible to use angiogenesis inhibitors, such as angiostatin (angiostatin), endostatin (endostatin).
The release of the progestogen (progestin) should preferably last from 1 to 10 years or from 1 to 5 years, or preferably from 3 to 5 years, and the release of the other drug should last from at least 1 week up to 5 years, or from 1 week to 1 year, or preferably from 1 week to 6 months.
The amount of therapeutically active substance (progestogen and therapeutically active substance capable of preventing or inhibiting endometrial bleeding) incorporated into the delivery system will vary depending on the particular therapeutically active agent and the time the intrauterine system is intended to provide treatment. There is no critical upper limit to the amount of therapeutically active agent incorporated into the device, as the upper limit may be varied and modified depending on the selected body configuration, the size, shape and number of reservoirs for the administered dose. The lower limit depends on the efficacy of the therapeutically active agent and the expected release time.
The delivery system of the present invention provides a sufficient amount and a sufficient release rate of the therapeutically active compounds for contraception and/or hormone therapy and for inhibiting or preventing endometrial bleeding. Such sufficient amounts and release rates are understood to mean that a safe and sufficiently effective amount of the compound is released at each time point throughout the desired release period. In particular, the release profile of the progestagen compound should not be too steep. The average release required will depend on the application. In another embodiment for contraception, the mean release may not be too low. The amount of therapeutically active agent required for each particular application of the delivery system can be readily determined by one skilled in the art.
The therapeutic dose of the active substance for reducing menstrual bleeding should be adjusted for its local activity on the endometrium. If released from the intrauterine system, a significantly lower dose than required for systemic administration is sufficient. These lower doses must range from the pharmacological equivalent of tranexamic acid administered orally daily to a total dose of 4-6 g.
The amount of progestogen or substance having progestogenic activity and the amount of therapeutically active substance capable of preventing or inhibiting endometrial bleeding preferably vary from about 0 to 60% by weight, preferably from 5 to 50% by weight when incorporated into the core matrix. Other possible ranges for the therapeutically active dose are 0.5-60 wt%, 5-55 wt%, 10-50 wt%, 25-60 wt%, 40-50 wt% and 5-40 wt%.
Manufacture of intrauterine delivery systems
The shape and size of the delivery systems discussed in this application can be selected by one skilled in the art within the size range of the uterine cavity. It will also be apparent that the system of the present invention can be designed for application to humans as well as mammals.
The intrauterine delivery system preferably comprises a body forming the framework of the system and a reservoir containing the therapeutically active substance attached to the body. A commonly used intrauterine system is a T-shaped object made of any biocompatible material and consisting of an elongated member having at one end a transverse member comprising two arms, the elongated member and the transverse member forming a substantially T-shaped piece when the system is placed in the uterus. The drug-loaded reservoir may be attached to the elongated member, to the cross member, or to both the elongated member and the cross member. The body of the intrauterine system may naturally have various other forms, e.g. a continuously curved shape, such as a circle, an angle, an ellipse, a shield or a polygon, as long as its shape and size are adapted to the size and geometry of the endometrial cavity.
Although the manufacture of such systems is well known in the art, it is discussed below.
The body and reservoir may be manufactured simultaneously or separately and subsequently assembled. The body is preferably manufactured by injection molding or compression molding. The drug-containing core may be manufactured by mixing the therapeutically active substance into a core matrix material, such as Polydimethylsiloxane (PDMS) or a component forming a polymer composition as defined above, which is processed into the desired shape by molding, casting, extrusion or by any other suitable method known in the art.
The film layer (if any) may be applied to the core according to known methods, such as by using extrusion or injection molding methods, spraying or dipping. Alternatively, the pre-formed film tube may be expanded mechanically, for example with a suitable device or by using, for example, a compressed gas such as air or by expanding it in a suitable solvent such as cyclohexane, diglyme (diglyme), isopropanol or a mixture of solvents, after which the expanded film tube is mounted on the core. When the solvent evaporates, the film is secured to the core.
Different methods can be used to secure the reservoir to the frame. For example, the carcass may comprise an elongated extension in the form of a metal or polymer shaft, core, rod or pin or the like at a suitable point, preferably the hollow tubular reservoir is assembled on the extension by first expanding the diameter of the reservoir tube to a certain extent (e.g., by expansion using pressure or solvent) and thereafter by simply sliding the reservoir onto the extension or inserting the extension into the hollow reservoir. It is also possible to first assemble the hollow tubular core to the body and then the membrane to the core. Other methods of attaching the reservoir to the frame include, for example, known welding techniques, the use of adhesives or the use of special metal or polymer inserts, clamps, connectors, adapters, clothespin-type assemblies or clamps, or the like.
If necessary, the reservoir thus obtained can be sealed at one or each end by using known techniques, for example by applying a drop of adhesive or silicone gel.
The delivery system may also be manufactured by coating the body with a drug-containing core material using known techniques (e.g., dipping, spraying, injection molding, and the like). According to a specific example in which the reservoirs are located one within the other, the delivery system may be manufactured, for example, by the following steps: the body is first coated with a progestagen-containing polymer layer, then with an optional film layer, and then the system is coated with a polymer layer comprising a therapeutically active substance capable of preventing or inhibiting endometrial bleeding and then with an outer film layer (if necessary).
Reservoirs in which the core consists of several parts or segments can also be prepared, for example, by using the co-extrusion process described in finnish patent FI 97947. The therapeutically active substance is mixed into the core matrix polymer composition and processed into the desired shape and size by using known extrusion methods. The film layer may then be applied to the preformed core by: each core segment is fed into an extruder, and then another segment without any active ingredient is fed or an empty space filled with air is left between the segments, which space will be filled with a film material during the extrusion process to form a separation film.
The system body may further include specific locking components to keep the core or reservoir in place during the insertion step, during device use, or during device removal. To improve the visualization and detection of the intrauterine system, e.g. in X-ray or ultrasound examinations, the system may comprise an inert metal clip, ring or sleeve on the body or reservoir, or an inert metal coating on at least a part of the body, or a metal powder, metal particles or X-ray contrast agent mixed with the raw materials of the body, core matrix or membrane of the system during the compounding step, or a metal loop anchored to the body of the IUS.
The delivery system of the present invention can be made in any size as desired, the exact size depending on the mammal and the particular application. In practice, the size of the delivery system should approximate the size of the uterine cavity. For women, the length of the IUS body is typically about 20mm to 40mm long, preferably 25mm to 38mm, and the width of the body is about 20mm to 32mm, which generally corresponds to the width of the bottom of the endometrial cavity. The body member has a cross-sectional diameter of about 1mm to 4mm, preferably 1.5mm to 3 mm.
The core length of the drug delivery system is selected to obtain the desired efficacy. The ratio of core lengths will depend on the particular therapeutic application, including the desired ratio and dosage of each drug to be delivered. The length of the reservoir and core section may be, for example, 1mm to 35 mm. The length of the placebo segment separating the reservoir or core segment can generally vary between 1-5mm and depends on the material properties and its ability to prevent penetration of the active substance.
The thickness of the separation membrane may be about 0.2mm to 5 mm. The thickness (i.e., the outer diameter of the core or core section) may be 0.1mm to 5.0mm, and preferably 0.2mm to 3.5 mm. The thickness of the film surrounding the core or core segments is 0.1mm to 1.0mm, preferably 0.2mm to 0.6 mm.
Experimental part
The following non-limiting examples describe the invention in more detail.
Example 1
Core preparation
45 parts by weight of levonorgestrel, 10 parts by weight of tranexamic acid and 50 parts by weight of poly (dimethylsiloxane-co-vinylmethylsiloxane) and 1.2 parts by weight of dichlorobenzoyl peroxide-polydimethylsiloxane slurry (50% dichlorobenzoyl peroxide) were mixed using a two-roll mill. The mixture was extruded into a tubular form with a wall thickness of 0.8mm and an outer diameter of 2.8mm and cured by heating at +150 ℃ for 15 minutes, during which time crosslinking occurred. The crosslinked core was cut into 24mm lengths.
Delivery system preparation
The core was expanded in cyclohexane and pulled onto the IUS body. The cyclohexane was evaporated.
Example 2
Core preparation
50 parts by weight of levonorgestrel, 50 parts by weight of poly (dimethylsiloxane-co-vinylmethylsiloxane) and 1.2 parts by weight of dichlorobenzoyl peroxide-polydimethylsiloxane slurry (50% dichlorobenzoyl peroxide) were mixed using a two-roll mill. The mixture was extruded into a tubular form with a wall thickness of 0.8mm and an outer diameter of 2.8mm and cured by heating at +150 ℃ for 15 minutes, during which time crosslinking occurred. The crosslinked core was cut into 15mm lengths.
The second core was prepared in a similar manner by using 10 parts by weight of danazol instead of levonorgestrel. The crosslinked core was cut into 8mm lengths.
Film preparation
99 parts of silica-filled poly (dimethylsiloxane-co-vinylmethylsiloxane), 10ppm of Pt catalyst (catalyst for the reaction mass) and 0.03 part of inhibitor (ethynylcyclohexanol) and about 0.6 part of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill. Based on the method described in FI97947, the film material is coextruded into a tubular form by simultaneously inserting the two cores prepared above through internal orifices in a mold, leaving empty spaces between the cores to be filled with the film material. The thickness of the film was 0.23 mm. The thickness of the separation film formed between the cores was 1.8 mm.
Example 3
Core preparation
In a kneader 54 parts of a commercial poly (dimethylsiloxane-co-vinylmethylsiloxane), 45.5 parts by weight of levonorgestrel, 0.4 parts of a poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker, 0.02 parts of an ethynylcyclohexanol inhibitor and 10ppm of a Pt catalyst (catalyst for the reaction mass) were mixed in vinyl-methyl-siloxane. The mixture was extruded into a tubular form with a wall thickness of 0.7mm and solidified by heating at +115 ℃ for 30 minutes and cooled.
The second core was prepared in a similar manner by using 79.5 parts of commercially available poly (dimethylsiloxane-co-vinylmethylsiloxane) and replacing levonorgestrel with 20 parts by weight of mefenamic acid.
Film preparation
9 parts of α, ω -divinyl ether end-capped poly (oxyethylene) -b-poly (dimethylsiloxane) multiblock copolymer (PEO-b-PDMS), 89 parts of silica-filled poly (dimethylsiloxane-co-vinylmethylsiloxane), 10ppm of Pt catalyst (catalyst for the reaction mass), 0.03 parts of inhibitor (ethynylcyclohexanol), and about 2 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill. The mixture was extruded into a tubular form with a wall thickness of 0.2mm and cured by heating.
Delivery system preparation
The film was allowed to swell in isopropanol and was drawn onto two cores. The isopropanol was evaporated. The reservoir containing levonorgestrel was cut to 22mm length and the reservoir containing mefenamic acid was cut to 4mm length. The tubular reservoir was then expanded in cyclohexane and assembled on the vertical stem of the T-shaped body by separating the reservoirs from each other by silver rings having substantially the inner diameter of the vertical stem and an outer diameter just slightly smaller than the outer diameter of the reservoir. The cyclohexane was evaporated again.
Example 4
Core preparation
In a two-roll mill 29 parts PEO-b-PDMS, 29 parts poly (dimethylsiloxane-co-vinylmethylsiloxane), 10ppm Pt catalyst (catalyst for the reaction mass), 0.02 parts inhibitor (ethynylcyclohexanol), and about 2.4 parts poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed and 39 parts levonorgestrel were added. The mixture was extruded into a tubular form with a wall thickness of 0.8mm and an outer diameter of 2.8mm and cured by heating at +150 ℃ for 15 minutes, during which time crosslinking occurred. The crosslinked core was cut into 12mm lengths.
The second core was prepared in a similar manner by using 20 parts by weight of mefenamic acid instead of levonorgestrel. The crosslinked core was cut into 10mm lengths. The third core (placebo segment) was prepared in a similar manner but without the addition of any active. The crosslinked core was cut into 3mm lengths.
Film preparation
9 parts of PEO-b-PDMS, 89 parts of silica-filled poly (dimethylsiloxane-co-vinylmethylsiloxane), 10ppm of Pt catalyst (catalyst for the reaction mass), 0.03 parts of inhibitor (ethynylcyclohexanol), and about 2 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill. The film material was extrusion coated onto the three cores prepared above by inserting them sequentially through the internal injection ports of the mold (in the order of levonorgestrel core, placebo, mefenamic acid core). The thickness of the film wall formed was 0.22 mm.
Example 5
Core preparation
24 parts of PEO-b-PDMS, 24 parts of poly (dimethylsiloxane-co-vinylmethylsiloxane), 10ppm of Pt catalyst (catalyst for the reaction mass), 0.02 part of inhibitor (ethynylcyclohexanol), and about 2.4 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill and 35 parts of levonorgestrel and 14.5 parts of mefenamic acid were added. The mixture was extruded into a tubular form with a wall thickness of 0.8mm and an outer diameter of 2.8mm and cured by heating at +150 ℃ for 15 minutes, during which time crosslinking occurred. The crosslinked core was cut into 24mm lengths.
Film preparation
100 parts by weight of poly (trifluoropropylmethylsiloxane-co-vinylmethylsiloxane) filled with silica, in which the content of trifluoropropylmethylsiloxane units was 99 mol%; i.e., the degree of trifluoropropyl substitution was 49.5%, and 1.2 parts by weight of dichlorobenzoyl peroxide-polydimethylsiloxane slurry (50% dichlorobenzoyl peroxide) were mixed with a two-roll mill. The mixture was extruded into a tubular form with a wall thickness of 0.22mm and cured by heating.
Delivery system preparation
The film was allowed to swell in isopropanol and was drawn onto the core. The solvent was allowed to evaporate. The tubular reservoir was then expanded with cyclohexane and fitted over the T-shaped IUS body. The cyclohexane was evaporated again. The reservoir ends were sealed using silicone gel.
Preparation of the delivery System, examples 2 and 4
The core-film reservoir was expanded in cyclohexane and the stem of the body was inserted into the hollow reservoir. The cyclohexane was evaporated again.
Drug release test
The release rate of the drug from the implant was measured in vitro as follows:
the intrauterine delivery system is attached in a vertical position to a stainless steel holder and the holder together with the device is placed in a glass vial containing 250ml of dissolution medium. The glass vial was shaken in a shaking water bath at 100rpm at 37 ℃. The dissolution medium was withdrawn at predetermined time intervals and replaced with fresh dissolution medium and the amount of drug released was analyzed using standard HPLC methods. The concentration of the dissolution medium and the timing of the medium changes (extraction and replacement) are selected to maintain the sink conditions during the test.
Although the present invention has been described in terms of particular embodiments and applications, other embodiments and modifications may be devised in light of this teaching by those of ordinary skill in the art without departing from the spirit or scope of the claimed invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.