| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | January 5, 1999 |
| PATENT TITLE |
Intravaginal drug delivery devices for the administration of 17.beta.-oestradiol precursors |
| PATENT ABSTRACT | The invention relates to an intravaginal drug delivery device for administration to a female mammal of certain 17.beta.-oestradiol precursors at a substantially constant rate for a period of at least three weeks. The 17.beta.-oestradiol precursor is a 17.beta.-oestradiol moiety in which the, or each, hydroxyl group of the 17.beta.-oestradiol moiety is blocked by a blocking group, which blocking group is readily removed from the 17.beta.-oestradiol in vivo. The 17.beta.-oestradiol precursor must have either a solubility in liquid silicone of not less than 0.1 mg/100 ml or a standard k value of not less than 0.1 .mu.g/day/mm. The 17.beta.-oestradiol precursor must also have a solubility in distilled water of not less than 1 .mu.g/100 ml |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 3, 1997 |
| PATENT CT FILE DATE | December 19, 1995 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | June 27, 1996 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
I claim: 1. A cylindrical intravaginal drug delivery device suitable for administration to a female mammal, the device comprising a 17.beta.-oestradiol precursor in a biocompatible hydrophobic elastomeric polymer matrix, the device releasing the 17.beta.-oestradiol precursor in a substantially zero order pattern for at least three weeks, the precursor being a 17.beta.-oestradiol moiety in which the, or each, hydroxyl group of the 17.beta.-oestradiol moiety is blocked by a blocking group, the precursor having sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by a standard k value, in which k=2C.sub.S D.pi., of not less than 0.1 .mu.g/day/mm, the precursor having sufficient hydrophilicity as determined by a solubility in distilled water of not less than 1 .mu.g/100 ml, the, or each, blocking group being so linked to the 17.beta.-oestradiol moiety as to be readily removed from the 17.beta.-oestradiol moiety in vivo, and the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal when removed from the 17.beta.-oestradiol moiety in vivo wherein C.sub.S corresponds to the precursor's saturation solubility in the polymer matrix and D corresponds to the precursor's diffusion coefficient in the polymer matrix. 2. An intravaginal drug delivery device according to claim 1, in which the, or each, blocking group is an aliphatic C.sub.1-5 acyl group, with the proviso that, when the acyl group is acetyl, each hydroxyl group cannot be blocked with acetyl. 3. An intravaginal drug delivery device according to claim 2, in which the acyl group is the acyl moiety of a saturated monocarboxylic or dicarboxylic acid. 4. An intravaginal drug delivery device according to claim 3, in which the acyl group is selected from the group comprising formyl, acetyl, propionyl, butyryl, isobutyryl, oxalyl, malonyl, succinyl and glutaryl. 5. An intravaginal drug delivery device according to claim 2, in which the acyl group is the acyl moiety of an unsaturated monocarboxylic or dicarboxylic acid. 6. An intravaginal drug delivery device according to claim 5, in which the acyl group is selected from acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, maleoyl, fumaroyl, citraconoyl and mesaconoyl. 7. An intravaginal drug delivery device according to claim 1, in which the blocking group blocks the 3-hydroxyl group of the 17.beta.-oestradiol moiety. 8. An intravaginal drug delivery device according to claim 1, in which the blocking group blocks the 17-hydroxyl group of the 17.beta.-oestradiol moiety. 9. An intravaginal drug delivery device according to claim 7, in which the blocking group is selected from acetyl or propionyl. 10. An intravaginal drug delivery device according to claim 7, in which the precursor is 17.beta.-oestradiol-3-acetate or 17.beta.-oestradiol-3-propionate. 11. An intravaginal drug delivery device according to claim 8, in which the precursor is 17.beta.-oestradiol-17-acetate or 17.beta.-oestradiol-17-propionate. 12. An intravaginal drug delivery device according to claim 1, in which the device additionally includes a progestogen in the polymer matrix. 13. An intravaginal drug delivery device according to claim 12, in which the progestogen is selected from the group comprising norethisterone-17-acetate and levonorgestrel. 14. An intravaginal drug delivery device according to claim 1 suitable for inducing hyper-oestrogenism including fertility control, in which the polymer matrix forms a hollow annulus and the device is provided with a central member within the annulus and a sheath surrounding the polymer matrix. 15. A process for the preparation of a cylindrical intravaginal drug delivery device for release in a substantially zero order pattern for at least three weeks and suitable for administration to a female mammal, the process comprising the steps of: combining a 17.beta.-oestradiol precursor, the precursor being a 17.beta.-oestradiol moiety in which the, or each, hydroxyl group of the 17.beta.-oestradiol moiety is blocked by a blocking group; the precursor having sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by standard k value as defined hereinabove of not less than 0.1 .mu.g/day/mm, the precursor having sufficient hydrophilicity as determined by a solubility in distilled water of not less than 1 .mu.g/100 ml, the, or each, blocking group being so linked to the 17.beta.-oestradiol moiety as to be readily removed from the 17.beta.-oestradiol moiety in vivo; and the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal, when removed from the 17.beta.-oestradiol moiety in vivo, with a biocompatible hydrophobic elastomeric polymer, a suitable cross-linking agent and a curing catalyst to form a mix; and curing the mix to form a polymer matrix. 16. A process according to claim 15, in which the polymer matrix forms a hollow annulus and the process comprises the steps of forming a central member; combining the 17.beta.-oestradiol precursor with a polymer, a suitable cross-linking agent and a curing catalyst to form a mix and curing the mix to form the polymer matrix in the form of the hollow annulus surrounding the central member; and providing a sheath surrounding the polymer matrix. 17. An intravaginal drug delivery device suitable for administration to a female mammal, whenever prepared by the process claimed in claim 15. 18. A method of using a 17.beta.-oestradiol precursor in a cylindrical intravaginal drug delivery device for release in a substantially zero order pattern for at least three weeks, which method comprises the step of incorporating in the drug delivery device the 17.beta.-oestradiol precursor, wherein the 17.beta.-oestradiol precursor is a 17.beta.-oestradiol moiety in which the, or each, hydroxyl group of the 17.beta.-oestradiol moiety is blocked by a blocking group, the precursor has sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by a standard k value as defined hereinabove of not less than 0.1 .mu.g/day/mm, the precursor has sufficient hydrophilicity as determined by a solubility in distilled water of not less than 1 .mu.g/100 ml, the, or each, blocking group is so linked to the 17.beta.-oestradiol moiety as to be readily removed from the 17.beta.-oestradiol moiety in vivo, and the, or each, blocking group is so chosen as to yield a substance which is non-toxic to the female mammal when removed from the 17.beta.-oestradiol moiety in vivo. 19. A method of releasing a 17.beta.-oestradiol precursor in a substantially zero order pattern for a least three weeks, which method comprises the steps of: incorporating the 17.beta.-oestradiol precursor in a cylindrical intravaginal drug delivery device, the 17.beta.-oestradiol precursor being a 17.beta.-oestradiol moiety in which the, or each, hydroxyl group of the 17.beta.-oestradiol moiety is blocked by a blocking group, the precursor having sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by a standard k value as defined hereinabove of not less than 0.1 .mu.g/100 ml, the precursor having sufficient hydrophilicity, as determined by a solubility in distilled water or not less than 1 .mu.g/100 ml, the, or each, blocking group being so linked to the 17.beta.-oestradiol moiety as to be readily removed from the 17.beta.-oestradiol moiety in vivo, the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal when removed from the 17.beta.-oestradiol moiety in vivo; and inserting the drug delivery device into a vagina of a female mammal for the at least three weeks. 20. An intravaginal drug delivery device according to claim 1 suitable for alleviating or preventing symptoms associated with hypo-oestrogenism including hormone replacement therapy, in which the polymer matrix forms a core and the device is provided with a sheath surrounding the polymer matrix. 21. A process according to claim 15, in which the polymer matrix forms a core and the process additionally comprises the step of providing a sheath surrounding the polymer matrix. 22. An intravaginal drug delivery device suitable for administration to a female mammal, whenever prepared by the process claimed in claim 16. 23. An intravaginal drug delivery device according to claim 10, in which the precursor is 17.beta.-oestradiol-3-acetate. 24. An intravaginal drug delivery device according to claim 11, in which the precursor is 17.beta.-oestradiol-17-acetate. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
This invention relates to intravaginal drug delivery devices for the administration of 17.beta.-oestradiol precursors. The term "17.beta.-oestradiol precursor" is intended to embrace certain compounds which can be converted into 17.beta.-oestradiol, which compounds possess physicochemical and clinical properties as defined hereinbelow. In particular, the present invention relates to intravaginal drug delivery devices for the administration of a 17.beta.-oestradiol precursor at a substantially constant rate over a prolonged period for oestrogen-requiring conditions such that either the symptoms associated with hypo-oestrogenism may be alleviated or prevented or, alternatively, fertility is controlled. More particularly, the invention relates to, but is not limited to, an intravaginal drug delivery device for the administration of a 17.beta.-oestradiol precursor for hormone replacement therapy in the human female. Hypo-oestrogenism in the premenopausal human female may occur due to disease, oophorectomy or traumatic injury ›2!. In the postmenopausal human female, hypo-oestrogenism occurs as a natural consequence of the ageing process. Fertility control involves the administration of sufficient oestrogen to prevent ovulation, in effect, an induced hyper-oestrogenism. The description hereinafter primarily concerns the utility of intravaginal drug delivery devices of the invention for the alleviation or prevention of symptoms associated with hypo-oestrogenism, specifically, hormone replacement therapy, but it will be appreciated that the intravaginal drug delivery devices of the invention may also be used to induce hyper-oestrogenism, specifically, to prevent ovulation and, therefore, to act as a contraceptive. In the normal, healthy human female, 17.beta.-oestradiol is the principal oestrogen produced by the functioning premenopausal ovary, primarily in the ovulating follicle, during each menstrual cycle ›1!. Circulating 17.beta.-oestradiol levels vary during the monthly cycle in the premenopausal human female, being at their highest during the peri-ovulatory phase (about 1000 pmol per liter). As ageing progresses in the human female, ovulation becomes less frequent and less predictable, resulting in diminished production of 17.beta.-oestradiol. At the menopause, when irreversible failure of ovarian follicular activity occurs, 17.beta.-oestradiol production decreases dramatically to less than 20 .mu.g per day, giving circulating levels of 17.beta.-oestradiol in serum of less than 30 pg/ml ›2! (1 pg/ml is equivalent to 3.676 pmol/l, assuming a molecular weight of 272 for oestradiol) Non-oral 17.beta.-oestradiol preparations intended for use in hormone replacement therapy typically deliver plasma levels of 17.beta.-oestradiol corresponding to mean levels of the hormone in the premenopausal subject at days 6 to 8 (about 200 pmol per liter) and days 8 to 10 (about 360 pmol per liter) of the cycle. For the transdermal route, which is one non-oral route, these plasma concentrations correspond to a dose of 50 .mu.g per day (low dose) to 100 .mu.g per day (high dose). This is generally accepted as the desirable non-oral dosage range in order to provide efficaceous relief of postmenopausal symptoms whilst minimising potential toxicity ›1!. Hypo-oestrogenic (including postmenopausal) symptoms may be classified ›3! as: (a) Neuroendocrine symptoms, characterised by one or more of the following: hot flushes, night sweats, insomnia, mood changes, anxiety, irritability, loss of memory and loss of concentration. (b) Lower urinogenital tract symptoms, characterised by one or more of the following: genital tract atrophy, dyspareunia, loss of libido, urethral syndrome. (c) Miscellaneous symptoms, characterised by one or more of the following: joint aches, paraesthesia, dry skin, dry or brittle hair, brittle nails. In those cases where the combination of symptoms is sufficiently severe, it is well recognised that oestrogen hormone replacement therapy is indicated. In the postmenopausal human female requiring such therapy, the aim is to restore premenopausal oestrogen balance by delivering the natural oestrogenic hormone, 17.beta.-oestradiol, to the systemic circulation in a pattern that mimics its physiological secretion, that is, continuously and at a low but effectively constant rate ›4!. It is well recognised by practitioners that hormone replacement therapy, once initiated in the human female, may be necessary for many years extending from the onset of the menopause. A physiologically effective dose of 17.beta.-oestradiol, sufficient to provide effective control of all postmenopausal symptoms, is considered to be at least 50 .mu.g per day ›1!, although transdermal patches delivering as low as 25 .mu.g per day will elevate plasma oestradiol levels and are used in oestrogen replacement therapy. Oral administration of oestrogen, including 17.beta.-oestradiol, for hormone replacement therapy has a number of disadvantages ›1,5!: (a) Oral administration of a drug is followed, primarily, by absorption through the gastrointestinal tract, from where the blood flow is to the liver. Some 60-90% of orally administered drug will be metabolised during this first pass through the liver. As a result, oral oestrogen therapy results in oestrone, a less potent oestrogen, as the predominant circulating oestrogen. (b) Oral therapy involves bolus doses resulting in high initial oestrogen levels which are non-physiological, a non-steady state of circulating serum oestrogen and a non-physiological 17.beta.-oestradiol:oestrone ratio. Given the long-term nature of hormone replacement therapy, a drug delivery system that promotes improved patient compliance and convenience by reducing the dosing frequency or by requiring less frequent dosing is desirable. Various routes of oestrogen administration have been suggested, including transdermal, subcutaneous and intravaginal administration: Oestrogens are efficiently absorbed by the transdermal route. First pass effects are avoided and a physiological 17.beta.-oestradiol:oestrone ratio is maintained. Transdermal administration of 17.beta.-oestradiol is, therefore, preferable to the oral route ›4!. Patient compliance and convenience are also enhanced. However, the physical size of the transdermal drug delivery system is such that a new device must be used every few days. This can lead to fluctuations in circulating serum oestrogen levels, which is inconvenient and has possible compliance problems for the patient. Subcutaneous implantation of 17.beta.-oestradiol-loaded pellets provides therapy extending to several months and is therefore advantageous in respect of both patient compliance and convenience. However, subcutaneous implants have a number of disadvantages ›2!: (a) A surgical procedure is required for insertion of the pellets. (b) Infection can arise at the insertion site. (c) The pellets are difficult to remove in the event of a problem developing and any attempted removal requires a further surgical exploration of the site. Many of the problems associated with oestrogen delivery for hormone replacement therapy and other long-term oestrogen-requiring conditions can be overcome by intravaginal administration of oestrogen. It is well-known that steroids in general, including oestrogens, are efficiently and rapidly absorbed through vaginal mucosal epithelium ›6,7!. The vaginal route avoids undesirable first-pass hepatic metabolism. Delivery of oestrogen by the vaginal route is analogous to secretion of oestrogen into the systemic circulation by the ovary. Oestrogens may be administered intravaginally by the use of creams, solutions or vaginal tablets ›2!. However, to achieve controlled-release of the oestrogenic agent, sustained over at least one month in order to enhance both patient compliance and convenience, an intravaginal device, optionally in the shape of a ring, is the most suitable drug delivery device. The intravaginal ring can be self-inserted high into the vagina where it is held in place. U.S. Pat. No. 3,545,439 discloses an intravaginal ring fabricated from a biocompatible organopolysiloxane elastomer and containing the steroidal compound medroxyprogesterone acetate for the purpose of providing contraception in the human female. There is no teaching that such a device can be used for the administration of 17.beta.-oestradiol precursors at a substantially constant (or zero order pattern) rate for a period of at least three weeks, for the treatment of long-term oestrogen-requiring conditions in general or, more specifically, for hormone replacement therapy. An article by Jackanicz ›8! teaches that three basic designs of intravaginal ring are possible, though additional design variations do exist: (a) The homogeneous ring, in which the steroid is homogeneously distributed in a hydrophobic elastomeric system, typically a grade of Silastic (Trade Mark), which is commercially available from Dow Corning. In this design, a high drug loading is possible and, consequently, comparatively large daily release rates are achievable over prolonged periods. However, this design is associated with an initial high release of drug, producing a non-physiological level of the circulating steroid in the plasma, followed by a decline in the drug release rate as the outer portions of the ring are depleted of drug. Consequently, this design of ring cannot achieve the desired pattern of a controlled, substantially constant drug release rate, which will be recognised by those skilled in the art as zero order pattern release, over a sustained period of at least three weeks, preferably several months. (b) The shell design, in which the steroid is contained in a narrow band or hollow annulus between a non-medicated central hydrophobic elastomeric core or central member and a narrow, outer non-medicated hydrophobic elastomeric sheath. The outer sheath acts as a metering, or rate-controlling, membrane. With this design, burst effects are reduced compared to the homogeneous ring. However, this design has the disadvantage that the drug reservoir is physically limited in size and the relative diameters of core, steroid band and rate-controlling sheath are such that, where comparatively high daily drug release rates are required, as in hormone replacement therapy, this design cannot achieve the desired pattern of a controlled, substantially constant comparatively high daily drug release rate for the desired period of at least three weeks, preferably several months. The shell design is, therefore, most suitable for contraception. (c) The core design, in which the steroid is homogeneously mixed with a hydrophobic elastomeric polymer to form a homogeneous core, the core being surrounded by a rate-controlling, non-medicated hydrophobic elastomeric sheath. In this design high drug loadings are possible and the relative diameters of core and rate-controlling sheath are such that a higher drug release rate can be achieved compared to the shell design. Burst release of drug is reduced, but not necessarily eliminated, as compared to the homogeneous ring design. Substantially zero order release can be achieved due to the presence of a rate-controlling sheath and such release can be sustained for several months due to the higher drug loading possible with this design. Intravaginal elastomeric rings designed to deliver 17.beta.-oestradiol for use in hormone replacement therapy are known. For example, a report by Englund and co-workers ›9! discloses an intravaginal elastomeric ring of shell design releasing in vitro 17.beta.-oestradiol at a rate of 200 .mu.g per day, which corresponds to plasma 17.beta.-oestradiol levels in human female patients of from 50 to 200 pg per ml. In this report, it is further disclosed that all of the human female subjects participating in the study had non-physiologically high 17.beta.-oestradiol plasma levels in the first 24 hours of the study period and that there was a gradual decline in the plasma oestradiol levels over the study period of 21 days. There is no teaching in this study that substantially constant plasma levels of 17.beta.-oestradiol can be maintained even within the comparatively short-term study period of 21 days, nor is there any teaching to suggest that the device could be used for the delivery of a suitable 17.beta.-oestradiol precursor compound. This study, however, does state that a 17.beta.-oestradiol release rate of 200 .mu.g per day is too high for hormone replacement therapy in post-menopausal women as the resulting plasma levels of 17.beta.-oestradiol are non-physiological, that is, they exceed the oestrogen levels seen in the follicular phase of fertile women. The authors conclude, in agreement with the teaching of Lievertz ›1!, that a device with a release rate of 50-100 .mu.g per day of 17.beta.-oestradiol would provide an appropriate dosage for hormone replacement therapy. A study by Roy and Mishell ›10! discloses an elastomeric intravaginal ring comprising a polymer matrix containing a combination of levonorgestrel and 17.beta.-oestradiol in dimethylpolysiloxane. This study teaches that 17.beta.-oestradiol has a lower solubility in, and diffusion from, the dimethylpolysiloxane elastomer than levonorgestrel. The ring design in this example was of the shell type, which had an outer diameter of 58 mm and a thickness of 9.5 mm, and released 290 .mu.g per day of levonorgestrel and 180 .mu.g per day of 17.beta.-oestradiol, respectively. The rings were studied over six or seven consecutive 21-day cycles. In each case, 17.beta.-oestradiol absorption produced an initial peak for the first few days of each cycle, after which plasma levels declined rapidly. The initial 17.beta.-oestradiol serum peak was due to burst release from the outer sheath, rather than from the polymer matrix, the burst effect then building up again during each week of storage between cycles. Thus, the ring design disclosed in this study is unsuitable for sustained delivery of 17.beta.-oestradiol for oestrogen-requiring conditions, including hormone replacement therapy. A study by Stumpf et al ›11! on hypo-oestrogenic women discloses an intravaginal ring of shell design intended specifically for use in hormone replacement therapy. The ring was 9.5 mm in cross-section and 54 mm in diameter. The steroid band or hollow annulus contained either 100, 200 or 400 mg of 17.beta.-oestradiol. One hour after insertion, mean serum 17.beta.-oestradiol was raised to 300 pg/ml, characteristic of a burst release of steroid, but approached the baseline level of 24 pg/ml within 24 hours. Over 1 month, the mean 17.beta.-oestradiol level increased minimally to about 50 pg/ml, falling back to the baseline at 2 and 3 months. The authors concluded that this design fails to provide effective therapeutic delivery of 17.beta.-oestradiol over a sufficiently long period as desired for hormone replacement therapy. Stumpf et al ›11! also discloses an alternative intravaginal ring of homogeneous design, comprising a polymer matrix containing 400 mg of 17.beta.-oestradiol in polydimethylsiloxane. This ring had a surface area of 22 cm.sup.2 and a cross-sectional area of 48 mm.sup.2. With this ring design, the initial serum 17.beta.-oestradiol level was raised to about 700 pg/ml within one hour, with the level maintained above 300 pg/ml for at least the first week of administration. Despite the authors' conclusion that this ring design maintains physiological oestradiol levels, it will be recognised by those skilled in the art that such levels of 17.beta.-oestradiol are non-physiological and, therefore, unacceptable for use in the human female requiring hormone replacement therapy. European Patent Publication No. 0 253 109 discloses an intravaginal ring of core design capable of delivering 17.beta.-oestradiol at rates per 24 hours varying from 0.5 to 25 .mu.g per day, preferably from 4 to 8 .mu.g per 24 hours, as selected. According to the teaching therein, symptoms in the human female arising from a hypo-oestrogenic condition can be alleviated by 17.beta.-oestradiol delivered at these rates. These rates of 17.beta.-oestradiol delivery are substantially lower than those generally recognised as being required to alleviate all of the possible symptoms associated with a hypo-oestrogenic condition--a daily delivery rate, as determined in vitro, of between 50 and 100 .mu.g of 17.beta.-oestradiol is generally accepted by those skilled in the art as necessary for effective hormone replacement therapy ›1! ›9! ›11! ›12!. The symptoms referred to in EP-A-0 253 109 relate exclusively to symptoms associated with the lower urinogenital tract. There is no teaching that such a low daily delivery rate of 17.beta.-oestradiol can relieve neuroendocrine and other miscellaneous symptoms associated with hypo-oestrogenism in the human female. Smith et al ›13! teaches that daily delivery of 17.beta.-oestradiol at a rate of between 5 and 10 .mu.g per day, as determined in vitro, is effective at alleviating those symptoms associated with hypo-oestrogenism that relate specifically to atrophy of vaginal and urethral epithelium. There is no teaching that other symptoms associated with hypo-oestrogenism are relieved by such low daily doses of 17.beta.-oestradiol. A number of difficulties arise in incorporating 17.beta.-oestradiol into intravaginal drug delivery devices. Specifically, the drug is too polar in its chemical character to be practically delivered in sufficient daily quantities to alleviate all of the clinical symptoms typically associated with hypo-oestrogenism in the human female and, most particularly, in postmenopausal females requiring hormone replacement therapy with oestrogen. These difficulties mean that a daily drug release in excess of 50 .mu.g of 17.beta.-oestradiol, as determined in vitro, an amount clinically acknowledged as necessary for effective hormone replacement therapy, cannot be practically achieved since: A narrow sheath surrounding a large diameter polymer matrix is difficult to mass produce reliably to acceptable limits by methods presently known in the art. A high drug concentration is required in the polymer matrix of the device, which consequently must be of large diameter. Thus, such devices are uneconomic to produce. The high drug residue left after use raises environmental concerns. It is not possible to include an additional active ingredient in known intravaginal drug delivery devices, typically a progestogen. According to a first aspect of the invention there is provided an intravaginal shell or core drug delivery device suitable for administration to a female mammal, the device comprising a 17.beta.-oestradiol precursor as defined hereinbelow in a polymer matrix and having a sheath surrounding the polymer matrix, said device being adapted to release the 17.beta.-oestradiol precursor in a substantially zero order pattern for at least three weeks, preferably for at least three months and to release up to 1 mg/day 17.beta.-oestradiol. The 17.beta.-oestradiol precursor must: be a 17.beta.-oestradiol moiety in which the, or each, hydroxyl group of the 17.beta.-oestradiol moiety is blocked by a blocking group; the, or each, blocking group being so linked to the 17.beta.-oestradiol moiety as to be readily removed from the 17.beta.-oestradiol moiety in vivo and the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal, when removed from the 17.beta.-oestradiol moiety in vivo. have sufficient lipophilicity as defined hereinbelow. have sufficient hydrophilicity as defined hereinbelow. Specifically, the 17.beta.-oestradiol precursors must have sufficient lipophilicity as determined directly by measurement of their solubilities in liquid silicone (Dow Corning Grade 360 Medical Fluid) at 37.degree. C. such that their solubilities must be not less than 0.1 mg per 100 ml or, alternatively, as determined indirectly by measurement of standard k (to be defined hereinafter) such that standard k must be not less than 0.1 .mu.g/day/mm. Such lipophilicity is required to ensure adequate diffusion of the precursor through the device. Specifically, the 17.beta.-oestradiol precursors must have sufficient hydrophilicity such that their solubilities in distilled water at 20.degree. C. are not less than 1 .mu.g per 100 ml. Such hydrophilicity is required to ensure that an adequate concentration of the precursor is achieved in the aqueous diffusion layer between the device and the vaginal epithelium. Precursor release from a cylindrical device of core design, which comprises a polymer matrix in the form of a core incorporating 17.beta.-oestradiol precursor and a sheath surrounding the core, can be described by Crank's equation: ##EQU1## in which R=precursor release rate (.mu.g/day) C.sub.S =saturation solubility of precursor in polymer matrix (.mu.g/ml) D=diffusion coefficient of precursor in polymer matrix (cm.sup.2 /day) .pi.=partition coefficient of precursor between polymer matrix and the dissolution medium l=core length (mm) b=sheath cross-sectional diameter (mm) a=core cross-sectional diameter (mm) Crank's equation relates the precursor release rate (R), in sink conditions, to the solubility (C.sub.2 S) and diffusibility (D) of the precursor in the polymer matrix, its partition characteristics (.pi.) between the polymer matrix and the dissolution medium; and the ring dimensions (l, b, a). For any given precursor in any given polymer matrix, C.sub.S, D and .pi. will be constant and can be grouped together to form the composite constant, k: k=2C.sub.S.D..pi. The k value can be empirically derived using Crank's equation in the following manner: ##EQU2## The k value is dependent on core length for certain of the 17.beta.-oestradiol precursors (see Example 6 hereinafter). Accordingly, the k value at a core length of 35 mm has been denoted "standard k" value hereinafter. The use of 17.beta.-oestradiol precursors with enhanced lipophilicity, relative to 17.beta.-oestradiol itself, is one parameter involved in overcoming the difficulties which arise in incorporating 17.beta.-oestradiol itself into intravaginal drug delivery devices. However, only 17.beta.-oestradiol precursors possessing the above-recited additional physicochemical property of sufficient hydrophilicity and clinical characteristics of ready in vivo conversion to 17.beta.-oestradiol without yielding toxic substances as a result of that conversion, are suitable for use in intravaginal devices for the delivery of therapeutic quantities of oestrogen to the human female for long-term oestrogen-requiring conditions, including hormone replacement therapy. In addition, such 17.beta.-oestradiol precursors are also suitable for fertility control. Thus, for example, 17.beta.-oestradiol-17-valerate, a highly hydrophobic precursor, will not give detectable blood levels of 17.beta.-oestradiol in the human female when delivered intravaginally from an intravaginal drug delivery device, since its hydrophilicity or aqueous solubility is too low. The invention therefore defines the characteristics of 17.beta.-oestradiol precursors, and identifies those suitable precursors, such that an intravaginal drug delivery device containing said precursors will deliver therapeutic quantities of 17.beta.-oestradiol to the female mammal without any of the disadvantages previously associated with such systems. Whilst it will be apparent that said intravaginal drug delivery device can have any shape and be of any dimensions compatible both with intravaginal administration to the female mammal, including the human female and with the requirements imposed by drug delivery kinetics, a particularly preferred device according to the present invention is an intravaginal ring. Said ring includes the outer, rate-controlling sheath surrounding the polymer matrix in the form of a core, which sheath may be fabricated from the same polymer as that of the polymer matrix or from any other suitable, compatible polymer known in the art. Alternatively, said ring includes the sheath surrounding the polymer matrix in the form of a hollow annulus and the device is provided with a central member within the annulus, which sheath and central member may each be fabricated from the same polymer as that of the polymer matrix or from any other suitable, compatible polymer known in the art. More preferably, daily release rates of the 17.beta.-oestradiol precursor equivalent to up to 1 mg per day of 17.beta.-oestradiol itself can be sustained for up to at least 12 months in a substantially zero order pattern. Preferably, said intravaginal drug delivery device additionally includes a progestogen in the polymer matrix, the progestogen being selected from the group comprising norethisterone-17-acetate and levonorgestrel. Said 17.beta.-oestradiol precursor can be delivered in a substantially zero order pattern for durations of at least three weeks and, preferably, up to 12 months at rates of delivery equivalent to up to 1 mg per day of 17.beta.-oestradiol itself and said progestogen can be delivered for a similar duration at rates of delivery of up to 1 mg per day. According to a second aspect of the invention there is provided use of a suitable 17.beta.-oestradiol precursor as defined hereinbefore for the manufacture of an intravaginal shell or core drug delivery device for daily release of up to 1 mg 17.beta.-oestradiol in a substantially zero order pattern for at least three weeks and, preferably, for up to 12 months for treating hypo-oestrogenic symptoms. The diameter of a rate-controlling sheath is such that it can be manufactured within acceptable tolerances by methods presently known in the art. According to a third aspect of the invention there is provided a process for the preparation of an intravaginal shell or core drug delivery device suitable for administration to a female mammal. Said process comprises the steps of combining a suitable 17.beta.-oestradiol precursor as defined hereinabove, a polymer, a suitable cross-linking agent and a curing catalyst to form a mix; curing the mix to form the polymer matrix; and providing a sheath surrounding the polymer matrix. Alternatively, the polymer matrix forms a hollow annulus and the process comprises the steps of forming a central member; combining the 17.beta.-oestradiol precursor with the polymer, the suitable cross-linking agent and the curing catalyst to form the mix and curing the mix to form the polymer matrix in the form of the hollow annulus surrounding the central member; and providing the sheath surroundiong the polymer matrix. The relative amounts of the respective polymer matrix and sheath components are chosen, and the geometry of the ring components selected, in order to provide a daily release of 17.beta.-oestradiol precursor equivalent to between 50 and 250, and most preferably between 50 and 100, .mu.g per day of 17.beta.-oesstradiol. According to a fourth aspect of the invention there is provided use of a suitable 17.beta.-oestradiol precursor as defined hereinabove in an intravaginal shell or core drug delivery device for release of up to 1 mg/day 17.beta.-oestradiol in a substantially zero order pattern for at least three weeks and, preferably, for up to 12 months. According to the present invention, a particularly preferred group of 17.beta.-oestradiol precursors are those possessing one or more acyl groups esterically linked as blocking groups to the hydroxyl groups of the 17.beta.-oestradiol moiety. Preferably, the, or each, blocking group is an aliphatic short-chain acyl group with the proviso that, when the acyl group is acetyl, each hydroxyl group cannot be blocked with acetyl. More preferably, the acyl group is the acyl moiety of a saturated or unsaturated monocarboxylic or dicarboxylic acid. The one or more acyl groups may block the 3-position and/or the 17-position of the 17.beta.-oestradiol moiety. It will be known to those skilled in the art that therapeutically active esters are rapidly hydrolysed in human plasma by non-specific esterases to the corresponding parent acid and alcohol. In the case of 17.beta.-oestradiol precursors, it will be apparent to those skilled in the art that hydrolysis of said precursors in human plasma will yield 17.beta.-oestradiol itself, together with one or more acidic components, the number of such acidic components depending on the number of acyl groups present per molecule of said precursor. Said acyl groups include saturated aliphatic short-chain (C1-5) straight or branched mono- and dicarboxylic acids such as formyl, acetyl, propionyl, butyryl, isobutyryl, oxalyl, malonyl, glutaryl and succinyl; unsaturated aliphatic short-chain (C2-5) straight or branched mono- and dicarboxylic acids such as acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, maleoyly fumaroyl, citraconoyl and mesaconoyl; carbocyclic carboxylic acids or other such groups known to those skilled in the art. Such acyl groups are disclosed by way of example only and it will be understood that the scope of the invention is not limited in any way by such disclosure. The preferred 17.beta.-oestradiol precursors must have sufficient lipophilic character such that their solubilities in liquid silicone (Dow Corning Grade 360 Medical Fluid) at 37.degree. C. are not less than 0.1 mg per 100 ml. Alternatively, the preferred 17.mu.-oestradiol ester precursors must have sufficient lipophilic character such that their standard k values (as defined hereinabove) are not less than 0.1 .mu.g/day/mm. Further, said precursors must have a hydrophilic character such that their solubilities in distilled water at 20.degree. C. are not less than 1 .mu.g per 100 ml. 17.beta.-oestradiol-3-benzoate and 17.beta.-oestradiol-17-valerate are examples of 17.beta.-oestradiol precursors not possessing the requisite aqueous solubility. Although not essential for the purposes of the invention, said precursors should, preferably, be micronised. According to the present invention, a preferred acyl group is acetyl or propionyl and particularly preferred 17.beta.-oestradiol precursors are 17.beta.-oestradiol-17-acetate, 17.beta.-oestradiol-3-acetate, 17.beta.-oestradiol-17-propionate and 17.beta.-oestradiol-3-propionate. According to the present invention, the acyl group preferably blocks the 3-position, so that particularly preferred 17.beta.-oestradiol precursors are 17.beta.-oestradiol-3-acetate and 17.beta.-oestradiol-3-propionate. 17.beta.-oestradiol-3-acetate is most particularly preferred. Suitable progestogens for use in the intravaginal drug delivery devices of the present invention include, but are not limited to, levonorgestrel and norethisterone-17-acetate. Further suitable progestogens would be expected to include chlormadinone, desorgestrel, gestodene, medroxyprogesterone, megestrol, norgestimate and progesterone. The intravaginal ring may be constructed from one or more biocompatible polymers, for example, elastomers, compatible with said 17.beta.-oestradiol precursors, such as organopolysiloxanes or polyurethanes. Where the elastomer is chosen from the room-temperature vulcanising type of hydroxyl-terminated organopolysiloxanes, suitable cross-linking agents and curing catalysts known in the art may be required. Dimethylpolysiloxane compositions may also be used as the elastomeric component of the intravaginal drug delivery device of the invention. The geometry of the intravaginal drug delivery device of the invention may be chosen such that the daily release of the 17.beta.-oestradiol precursor can be varied up to 1 mg per day, expressed as 17.beta.-oestradiol itself, and preferably from between 50 to 100 .mu.g per day, again expressed as 17.beta.-oestradiol itself. Said ring geometries can also be varied to permit the simultaneous delivery, at therapeutically desirable rates, from an individual intravaginal drug delivery device, of a suitable 17.beta.-oestradiol precursor and a progestogenic substance. The term "geometry" encompasses the overall diameter of the ring; the cross-sectional diameter of the ring; the ratio of the core diameter to the diameter of the whole device in cross-section; and the length of the core. The percentage loading of 17.beta.-oestradiol precursor contained in the core can vary from 1% (w/w) to in excess of 50% (w/w) and is only limited by the physical characteristics of the final mix. It will be apparent to those skilled in the art that the only importance of said drug loading in a device of core or shell design with an outer, rate-controlling sheath is to ensure that there is sufficient drug present at all times to allow a substantially zero order pattern of drug release to be maintained throughout the required period of sustained drug release. Thus, to ensure maintenance of the substantially zero order drug release pattern throughout the lifetime of the device, the necessary drug loading will be sufficiently in excess of the total drug required to be delivered over the defined sustained-release period. Several embodiments of the invention will now be demonstrated by reference to the following General Method of Manufacture of an intravaginal drug delivery device in the form of a ring for the delivery of a suitable 17.beta.-oestradiol precursor as defined hereinabove, either alone or in combination with a progestogenic substance. This General Method of Manufacture is exemplified by reference to Examples 1 to 10. It should be understood that these examples are disclosed solely by way of further illustrating the invention and should not be taken in any way to limit the scope of said invention. Thus, for instance, it will be obvious to those skilled in the art that the technique of injection moulding referred to in the General Method of Manufacture may be replaced in whole or in part by other manufacturing techniques, for example, extrusion, that will produce a similar end product. General Method of Manufacture: Core Design An elastomer mix is prepared by blending 97 parts by weight of a hydrophobic elastomeric polymer containing about 25% (w/w) diatomaceous earth as the filler with 2.5 parts by weight of a cross-linking agent, n-propylorthosilicate. A suitable hydrophobic elastomeric polymer is stannous octoate-cured polydimethylsiloxane polymer, two suitable examples of which are those known as Dow Corning QCF7 3099 and Nusil Med 7.6382. The elastomer mix thus formed is further blended in the ratio of 85 parts by weight of the elastomer mix, 5 parts by weight of barium sulphate and 10 parts by weight of a 17.beta.-oestradiol precursor, preferably a 17.beta.-oestradiol ester, more preferably, 17.beta.-oestradiol-3-acetate, 17.beta.-oestradiol-17-acetate, 17.beta.-oestradiol-3-propionate or 17.beta.-oestradiol-17-propionate. Thereby, an active mix is formed. The core of the intravaginal drug delivery device of the invention is produced by mixing 200 parts by weight of the active mix with 1 part by weight of an activating catalyst, for example, stannous octoate. The resultant core mix is injected into a core mould and cured at 80.degree. C. for 2 minutes. The mould is then opened, following which the core is removed and trimmed. An intravaginal drug delivery device in the form of a half ring is produced by mixing 200 parts by weight of elastomer mix with 1 part by weight of an activating catalyst, for example, stannous octoate. The resultant half ring mix is injected into a half ring mould containing a core previously prepared as described in the immediately preceding paragraph and cured at 80.degree. C. for 2 minutes. The mould is then opened, following which the half ring is removed and trimmed. An intravaginal drug delivery device in the form of a complete ring is produced by mixing 200 parts by weight of elastomer mix with 1 part by weight of an activating catalyst, for example, stannous octoate. The resultant full ring mix is injected into a full ring mould containing a half ring previously prepared as described in the immediately preceding paragraph and cured at 80.degree. C. for 2 minutes. The mould is then opened, following which the full ring is removed and trimmed. The geometric characteristics of the ring can be varied as required by the use of appropriately sized moulds, as exemplified by the following examples, or by the use of appropriately sized extrusion nozzles, as will be obvious to those skilled in the art. |
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