United States Patent:   6,103,256

Assignee:  Hoechst Marion Roussel (FR)

Filed:  December 2, 1999

An intravaginal drug delivery device comprising at least one active agent dispersed in a polymer matrix, wherein the concentration of active agent at the outer surface of the device at the time of use is not substantially higher than the concentration of the active agent in the remainder of the device, a method of treatment therewith and a process for its preparation.

BRIEF SUMMARY OF THE INVENTION

It has now surprisingly been found that wrapping an intravaginal drug delivery device with a removable polymer membrane is able to substantially reduce not only the initial high burst of active from the device following administration, e.g. during the first 24 hours of use, but also the levels of release of active during the first 3 weeks of use.

Thus, viewed from one aspect the invention provides an intravaginal drug delivery system having a first part intended for intravaginal administration ("an intravaginal part") comprising at least one active agent, such as an oestrogen and/or a progestogen, in a polymer matrix, said first part being provided in association with a second part comprising a removable polymer membrane arranged to absorb excess active agent.

By "removable" it is intended that the polymer membrane is arranged such that this can readily be removed from the intravaginal part by the patient or the physician prior to use or, alternatively, as an intermediate step during the manufacturing process. Conveniently, removal of the membrane may be achieved by simply tearing away the polymer membrane, for example along pre-formed tear lines or perforations provided in the membrane.

The polymer membrane may surround the intravaginal part either wholly or substantially. Preferably, the membrane wholly surrounds the intravaginal part.

Whilst not wishing to be bound by theoretical considerations it is believed that the initial high level of active released from vaginal rings of the core or shell design is a result of diffusion of the active from the surface of the core into the surrounding sheath during storage. This in turn results in an artificially high concentration gradient of active across the sheath and very close to the outer surface of the ring. Such an accumulation of active close to the surface of the ring is in excess of that which can be modelled using a matrix type distribution.

Similarly, it is believed that the high initial burst of active from rings of the matrix design is a result of a high level of active present on the surface of the ring. In these rings, the active is thus also believed to be present in much greater amounts at the outer surface of the ring.

Again not wishing to be bound by theory, it is believed that the polymer membrane serves to remove excess quantities of active from the surface of the intravaginal part of the system. This enables delivery of sustained, therapeutic quantities of active agent over extended periods of time, such as required in the delivery of oestrogen in Estrogen Replacement Therapy (ERT) and Hormone Replacement Therapy (HRT) or in the delivery of estrogens and progestogens in contraception, without any initial high burst of active.

In serving to effectively remove the high concentration of active at the outer surface of the intravaginal part of the system, the invention is capable of providing an intravaginal delivery device in which the active or actives are more homogeneously dispersed therein. Preferably, the active agent is substantially homogeneously dispersed throughout the polymer matrix.

Thus, viewed from another aspect the invention provides an intravaginal drug delivery device comprising at least one active agent, such as an oestrogen and/or a progestogen, dispersed in a polymer matrix, wherein the concentration of active agent at the outer surface of the device at the time of use is not substantially higher than the concentration of the active agent in the remainder of the device. Preferably, the active is substantially homogeneously dispersed throughout the device.

Yet more preferably, the concentration of active agent at the outer surface of the device is substantially lower than the concentration of the active agent in the remainder of the device. Thus, preferably the active is substantially homogeneously dispersed throughout the device, other than in close proximity to the surface.

Whilst it will be appreciated that the precise shape and dimensions of the polymer membrane will depend on the geometry of the device, the membrane should preferably be arranged such that this forms a relatively tight fit with the intravaginal part of the system. Thus, the polymer membrane should generally correspond to the shape of the intravaginal part. For example, in the case of a ring-shaped device the membrane will conveniently be toroidal in shape and its dimensions will be such that this lies in close contact with the outer surface of the intravaginal part.

The polymer membrane may be in direct contact with the intravaginal part. However, contact between the polymer membrane and the intravaginal part may be improved by smearing or coating the intravaginal part, either wholly or substantially, with an inert lubricant, e.g. a lubricating oil such as silicone, prior to wrapping with the polymer membrane. Examples of lubricants other than silicone which may be used to coat the intravaginal part prior to wrapping include other non-oxidising oils known to those skilled in the art. The use of a lubricant to coat the intravaginal part prior to wrapping also serves to aid ready removal of the polymer membrane by the patient or physician prior to use. Conveniently, any lubricant is removed from the intravaginal part, e.g. by washing, before use.

The polymer membrane may comprise any polymer material capable of absorbing an active from the intravaginal part and those skilled in the art will be aware of particular polymer materials suitable for this purpose. Whilst the particular choice of polymer for use as a membrane material will clearly depend on the active or actives to be delivered, polymers particularly suitable for use as a membrane material are those having a water vapour transmission (measured at a temperature of 20^oC., a relative humidity of 85% and a film thickness of 50 .mu.m) in the range of from 1 to 10,000 g/m².d, more preferably from 1 to 300 g/m².d, e.g. from 1 to 100 g/m².d (wherein d=24 hours).

In general, any biocompatible polymer or mixture of such polymers may be used as the membrane material. Particularly suitable polymer materials include polyolefins such as polyethylene, polypropylene and polymethylpentene. Other polymers which may be used as the membrane material include polyvinylchloride, polyurethanes, polyamides and silicone elastomers such as organopolysiloxanes. Particularly preferred polymers are organopolysiloxanes, such as polydimethylsiloxanes and polyvinylmethylsiloxanes or mixtures thereof, optionally containing one or more fatty acid esters.

The thickness of the polymer membrane for use in accordance with the invention is dependent upon a number of factors, including the size, shape and specific design of the device, the amount and type of drug present in the device, and the period over which the device is intended to be stored in the membrane prior to use. Whilst those skilled in the art can readily determine the desired thickness for the polymer membrane for any given device, this will conveniently lie in the range of from 10 to 3000 .mu.m, preferably from 10 to 2000 .mu.m, more preferably from 30 to 1000 .mu.m, e.g. from 30 to 100 .mu.m.

As mentioned above, the thickness of the polymer membrane will be determined by the design of the ring, i.e. whether this is of the matrix, core or shell design. The membrane will be thickest for use with a matrix-type ring where a thickness of from 10 to 3000 .mu.m is preferred. In the case of the core and shell designs, the use of a much thinner membrane is possible, e.g. one having a thickness of from 10 to 2000 .mu.m.

The polymer matrix and polymer membrane may comprise one or more biocompatible polymers, for example elastomers such as organopolysiloxanes. Preferred elastomers include hydroxyl-terminated organopolysiloxanes of the RTV (room temperature vulcanizing) type which harden to elastomers at room temperature following the addition of cross-linking agents in the presence of curing catalysts. Suitable cross-linking agents and curing catalysts are known in the art. A typical curing catalyst is stannous octoate. Curing temperature and curing times can vary within broad ranges and depend on the particular elastomer used. The curing temperature may vary between room temperature and 150^oC., but is preferably within the range of from 60 to 90^oC. The curing time may vary between a few seconds to several hours.

Other suitable elastomers include two-component dimethylpolysiloxane compositions which are platinum catalysed at room temperature or under elevated temperatures and capable of addition cross-linking.

Preferred hydrophobic elastomers for use either as the polymer matrix or the polymer membrane material in the device according to the invention include Silastic 382.RTM. and Silastic 4210.RTM., both commercially available from Dow Corning.

In a preferred embodiment of the invention, the intravaginal part of the device comprises a polymer matrix surrounded by a rate-controlling sheath through which the active can diffuse and which controls the rate of diffusion of active from the device into the vagina.

In a further embodiment of the invention, the intravaginal part comprises a core of inert elastomer, an active-containing polymer matrix encircling the core and an outer rate-controlling sheath through which the active can diffuse.

The sheath may comprise any bio-compatible polymer. Conveniently this will comprise the same polymer as the polymer matrix.

The polymer matrix and/or the rate-controlling sheath may further comprise one or more filler materials, such as diatomaceous earth or silica. In addition, the polymer matrix may comprise an X-ray contrast medium, such as barium sulphate, which can be used for identification purposes.

The polymer matrix, polymer membrane and/or the rate-controlling sheath may further comprise one or more rate modifying agents, such as a fatty acid ester, preferably one containing from 2 to 20 carbon atoms.

Preferred fatty acid esters for use in the device according to the invention include those formed from acids containing from 2 to 20 carbon atoms, especially long chain fatty acids, e.g. caproic, lauric, myristic, oleic, linoleic, adipic and lanolic acids. Particularly preferred are those esters formed from myristic acid. Alcohols which may be used in the formation of the esters include those containing from 2 to 20 carbon atoms, particularly those containing from 2 to 4 carbon atoms, e.g. propanol, in particular, isopropanol. A particularly preferred fatty acid ester is isopropyl myristate.

The amount of fatty acid ester present in the device will clearly depend upon the particular active to be delivered as well as the condition to be treated. Conveniently, the amount of fatty acid ester present in the device is from 1 to 50% by weight, preferably from 5 to 20% by weight. By suitable adjustment of the level of fatty acid ester present in the polymer matrix, a range of doses of active from rings of similar geometry can be achieved.

Whilst it should be apparent that the intravaginal device in accordance with the invention may have any shape and dimensions compatible with intravaginal administration, a preferred device according to the invention is in the form of a ring. This conveniently comprises a central annular polymer matrix core surrounded by an annular rate-controlling sheath.

Conveniently, the overall diameter of the ring is in the range of from 52 to 62 mm, with a sheath diameter (cross-sectional diameter of the ring) in the range of from 4 to 10 mm and a core diameter in the range of from 1 to 9 mm. The thickness of the rate-controlling sheath is such that it can be manufactured within acceptable tolerances by methods known in the art and conveniently lies within the range of from 1 to 4 mm, particularly from 1 to 3 mm. The geometry of the ring may be selected depending on the required daily dose of active and the duration of the course of treatment.

The intravaginal drug delivery device in accordance with the invention is considered to have utility in connection with the delivery of a wide range of therapeutic agents. As used herein, the terms "active" and "active agent" are used interchangeably and are intended to define any substance which in vivo is capable of producing a desired, usually beneficial, effect and may be an agent having either a therapeutic or a prophylactic effect.

Examples of active agents suitable for use in the device of the invention include agents in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics, antiviral and antifungal agents, analgesics, antidepressants, hormones and vitamins.

It will be appreciated that the desired amount of active agent present in the device will depend on the particular active being administered as well as the condition being treated. Convenient amounts of active, such as oestrogen, present in the device are from 1 to 50% by weight, preferably up to 15% by weight, more preferably from 5 to 15% by weight.

Conveniently, the device according to the invention can be used to effectively treat a number of conditions resulting from oestrogen deficiency, e.g. vasomotor symptoms associated with oestrogen deficiency, atrophic vaginitis, atrophic urethritis and osteoporosis associated with oestrogen deficiency. The device is particularly effective in hormone and oestrogen replacement therapies. Since fertility control involves the administration of sufficient oestrogen or progestogen to prevent ovulation, it will be appreciated that the delivery device-of the invention may also be used to prevent ovulation and thus act as an effective contraceptive. In this regard, the active may comprise one or more contraceptive steroids selected from ethinyl estradiol, levonorgestrel, d,l-norgestrel and norethindrone.

Oestrogens which can be delivered vaginally using the device according to the invention include oestrone and oestriol, in particular 17.beta.-oestradiol which is widely used in hormone replacement therapy (HRT). Constant, daily release rates up to 500 .mu.g per day for a period of up to 12 months can be achieved using a device in accordance with the invention. The desired rate of release of oestrogen depends on the condition to be treated but can be varied over a range of from 10 to 200 .mu.g per day. A physiologically effective dose of 17.beta.-oestradiol sufficient to treat postmenopausal symptoms is considered to be of the order of at least 50 .mu.g per day. For use as a contraceptive device, 20 .mu.g per day of levonorgestrel may be delivered.

Women who have undergone a hysterectomy with or without oophorectomy are at no risk from endometrial proliferation and can receive unopposed 17.beta.-oestradiol. However, for women with an intact uterus, 17.beta.-oestradiol therapy may conveniently be combined with a progestogen to reduce the risk of endometrial carcinoma.

Progestogens which can be delivered vaginally, either alone or in combination with an oestrogen, using the device according to the invention include any progestogens known to be suitable for use in hormonal replacement therapy and in contraception. Preferred progestogens include progesterone, medroxyprogesterone, norethisterone, norethisterone acetate and trimegestone. Convenient amounts of progestogen present in the device are from 1 to 50% by weight, preferably up to 15% by weight, more preferably from 5 to 15% by weight.

Other actives which can be administered using the device in accordance with the invention and their therapeutic use are listed by way of example only in the following table:

Claim 1 of 7 Claims

1. An intravaginal drug delivery device comprising at least one active agent dispersed in a polymer matrix, wherein the concentration of active agent at the outer surface of the device at the time of use is not substantially higher than the concentration of the active agent in the remainder of the device.

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