Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-05-01
2002-07-09
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S426000, C424S430000, C424S432000, C424S444000
Reexamination Certificate
active
06416780
ABSTRACT:
This invention relates to intravaginal drug delivery devices for the administration of testosterone and testosterone precursors to the human or animal female. The term ‘precursor’ is intended to embrace those compounds which can be readily converted in vivo into testosterone, in which the products of such conversion are clinically and toxicologically acceptable and which compounds possess certain physicochemical properties as defined hereinbelow. In particular, it relates to intravaginal drug delivery devices for the administration of testosterone or a testosterone precursor at a substantially zero order rate over a prolonged period to alleviate or prevent the symptoms associated with testosterone deficiency or, alternatively, to induce supratherapeutic levels.
The intravaginal drug delivery devices of the invention are particularly suitable for the alleviation or prevention of symptoms associated with testosterone deficiency either as a discrete treatment regimen or as an element of hormone replacement therapy in association with oestrogen or combined oestrogen/progestogen drug delivery devices. The clinical efficacy of testosterone replacement therapy, in association with exogenous oestrogen, has been reported from 1950 onwards [2]. The invention may, however, also have application to improve muscle mass and/or bone mass in patients with, for example, AIDS wasting syndrome or osteoporosis, respectively. In addition, the invention may have application as an antiproliferative agent for use against, for example, breast cancer, endometrial cancer, or endometriosis or, alternatively, to treat urogenital or vulval problems.
Plasma concentrations of testosterone in the normal, pre-menopausal, healthy human female are between 0.5 and 2.3 nM (0.15 to 0.65 ng per ml) with a mid-cycle peak [1]. Testosterone deficiency in the premenopausal human female may occur due to disease, oophorectomy, adrenalectomy or traumatic injury. In the postmenopausal female, testosterone deficiency arises primarily from a reduced adrenal output of androstenedione, which is peripherally converted to testosterone in vivo [1].
Testosterone may be administered by intramuscular injection as an oily solution or an aqueous suspension but, when administered by this route, testosterone is rapidly absorbed, metabolised and excreted. Testosterone esters are more hydrophobic than the free steroid and, consequently, are absorbed more slowly than testosterone from the intramuscular route. However, no rate-controlling mechanism is provided and intramuscular injection of a testosterone ester cannot, therefore, provide a substantially zero order pattern of release.
Following oral administration, testosterone or testosterone derivatives are readily absorbed but have poor efficacy because of considerable first-pass hepatic metabolism. Prolonged delivery for at least three weeks in a substantially zero order pattern of release cannot be achieved by the oral route.
GB-B-2 185 187 and GB-B-2 161 073 teach that testosterone may be absorbed across human scrotal skin from a flexible patch over, preferably, 24 hours. A matrix (or non-rate controlled) system for transdermal testosterone delivery to the human female is also known [3]. This system delivers about 1000 &mgr;g of testosterone per day, yielding mean circulating plasma testosterone levels of 4-6 nM. Transdermal administration avoids first-pass hepatic metabolism. However, the physical size of transdermal drug delivery systems is such that a new device must be used every few days. This can lead co fluctuations in circulating serum testosterone levels. Furthermore, frequent device replacement is inconvenient and has possible compliance problems for the patient. Although transdermal delivery systems that can maintain substantially constant delivery are known, it is not possible to maintain a substantially zero order delivery for at least three weeks by this route.
Subcutaneous implantation (50 or 100 mg) of testosterone-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. Specifically, a surgical procedure is required for both insertion and removal of the pellets. In addition, infection, pain and swelling can arise at the insertion site. Furthermore, due to physical size limitations of such systems, it is not possible to make testosterone implants that can deliver the hormone in a substantially zero order pattern over a prolonged period of at least three weeks.
It might be expected that many of the problems associated with long-term testosterone delivery in the human or animal female could be overcome by intravaginal administration of testosterone or testosterone precursors. The vaginal route avoids undesirable first-pass hepatic metabolism. Delivery of testosterone or a testosterone precursor by this route would be expected to be analogous to the natural secretion of testosterone per se into systemic circulation. To achieve substantially zero order pattern of testosterone release, sustained over a period of at least three weeks in order to enhance both patient compliance and convenience, an intravaginal drug delivery device might be expected to be the most suitable drug delivery device. However, there is no teaching of such a device to deliver testosterone at all.
Three basic designs of intravaginal ring are possible, though additional design variations do exist:
(a) The homogeneous or matrix ring, in which the drug is distributed in a polymer matrix. This design is associated with an initial high release of drug, producing a non-physiological circulating plasma level, followed by a decline in the drug release rate as the outer portions of the ring are depleted of drug. Consequently, this ring design cannot deliver the desired substantially constant (or zero order) drug release over a sustained period.
(b) The shell design, in which the drug is contained in a hollow annulus between a drug-free central member and a drug-free sheath or rate-controlling membrane. With this design, burst effects are reduced compared to the homogeneous ring. However, the drug reservoir is physically limited in size and the relative diameters of drug-free central member, hollow drug-containing annulus (polymer matrix) and rate-controlling sheath are such that, where comparatively high daily drug release rates are required, as in supratherapeutic testosterone therapy (e.g. testosterone replacement), this design cannot sustain drug delivery for the desired period of at least three weeks. This design can, of course, sustain drug delivery over at least three weeks, when lower daily drug release rates are required for other indications.
(c) The core design, in which the drug is contained in a core, surrounded by a rate-controlling, drug-free sheath. In this design, high drug loadings are possible and the relative diameters of core and sheath are such that a higher drug release rate can be achieved compared to the shell design. Burst release of drug is reduced compared to the homogeneous ring. Substantially zero order release can be achieved and such release can be sustained for at least three weeks and up to several months due to the higher drug loading possible with this design.
Although intravaginal drug delivery devices containing oestrogens and/or progestogens are long known in the art, there is no teaching in the literature of an intravaginal drug delivery device containing testosterone for any purpose. This is despite intravaginal drug delivery devices being well-known to those skilled in the art and the clinical benefits of testosterone administration being known for many years.
Prejudice against the incorporation of testosterone or a testosterone precursor in an intravaginal drug delivery device in the human or animal female may be at least partially explained by:
(a) The comparatively low apparent permeability coefficient of testosterone across vaginal epithelium, normalised with respect to that of me
Gilligan Claire
Passmore Clare
Carr Deborah D.
Galen (Chemicals) Limited
Maioli Jay H.
LandOfFree
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