WO1992018101A1

WO1992018101A1 - Vaginal drug delivery device

Info

Publication number: WO1992018101A1
Application number: PCT/US1992/002659
Authority: WO
Inventors: David Wade Osborne; Carolyn V. Pesheck
Original assignee: The Upjohn Company
Priority date: 1991-04-12
Filing date: 1992-04-08
Publication date: 1992-10-29
Also published as: AU1797592A

Abstract

A pharmaceutical preparation having improved sustained release properties is made up of a silicone elastomer matrix containing a pharmacologically active ingredient, a plasticizer and an osmotic modifier for the silicone elastomer. The pharmaceutical preparation can be provided in the form of a medicinal device which is inserted into a vaginal cavity to administer the pharmacologically active ingredient therein. The medicinal device can also be provided in the form of a modified annular ring which surrounds and engages with a body part contained within the vaginal cavity and has a flap attached at an end thereof to the annular ring in such a manner that a portion of an opening defined by the annular collar is covered by the flap. The pharmaceutical preparation is especially suited for the treatment of bacterial vaginosis.

Description

VAGINAL DRUG DELIVERY DEVICE BACKGROUND OF THE INVENTION This invention arises in the field of pharmaceutical preparations which are adapted for placement or implanta¬ tion into a living body and medicinal devices made of these pharmaceutical preparations. Such pharmaceutical prepara¬ tions typically comprise a matrix material which is inert in the environment of use and a medication which is to be released from the inert matrix at a controlled rate for a prolonged period of time. This type of pharmaceutical preparation is to be contrasted with other types of pharma¬ ceutical compositions which release the medication by solution of the substance used to transport the medication as in an oral or implanted tablet or an aqueous solution or like medicament.

It is well known that silicone polymers provide an inert' carrier matrix from which a pharmaceutically active material can be released into a surrounding environment. British Patent No. 1412969 discloses pharmaceutical prepa¬ rations containing a silicone elastomer matrix and a phar- macologically active substance which may be implanted or inserted into a part of the body at which it is desired for the pharmaceutically active substance to be released. British Patent Nos. 1528602 and 1581474 both show vaginal rings made of a silicone matrix material and a pharma¬ cologically active substance which is used in the preven¬ tion of conception. U.S. Patent Nos. 3 545 439 and 3 920 805 both disclose annular devices adapted for intra- vaginal placement and retention which are made of an or- ganopolysiloxane matrix and a pharmaceutically active substance which is.to be released into the surrounding en¬ vironment. U.S. Patent No. 4 411658 discloses a device used in the vaginal administration of a medicinal sub¬ stance which is provided in the form of a star and com¬ prises a silicone matrix and a pharmaceutically active substance which is contained in the matrix and released in the environment of use.

All of these prior art pharmaceutical preparations have a problem in that the amount of the medicament released from the silicone matrix is low and cannot be sustained for a prolonged period of time. As a result, it is necessary to frequently replace these pharmaceutical preparations with "fresh" preparations containing a high loading of the drug to be administered. This results in unnecessary expense and discomfort to the user since these pharmaceuti¬ cal preparations have to be frequently inserted and removed from the body part in which the medicament is to be re¬ leased.

There have recently been efforts directed to the im- provement of the release properties of silicone rubber based pharmaceutical preparations. Japanese Patent Ap¬ plication No. 57-153840 discloses the use of an elution promoting agent having a solubility in water greater than 10 percent in combination with a silicone rubber base and an active ingredient that has improved sustained release properties. As the elution promoting agents, salts such as sodium chloride and potassium chloride, organic acids and nonreducing sugars, such as annitol, sorbitol and xylitol are disclosed. However, the silicone rubber based sus- tained release preparations disclosed in this reference still are unable to release a large percentage of the phar¬ macologically active substance contained in the silicone rubber matrix into the environment of use over a prolonged period of time.

BRIEF SUMMARY OF THE INVENTION The present invention relates to an improved pharma¬ ceutical preparation comprising a silicone elastomer matrix, a pharmacologically active ingredient, a plasti¬ cizer and an osmotic modifier contained in the silicone matrix which is suited for placement within a living mam¬ malian body. The pharmacologically active ingredient diffuses from the silicone elastomer matrix in a large amount over a sustained period of time, is absorbed into the surrounding body fluids and exerts its desired effect in the surrounding environment. The silicone matrix is bio-compatible and completely inert in the environment of use and is removed in unchanged form when it is desired to terminate the treatment with the pharmacologically active ingredient or replace the "spent" matrix with a "fresh" matrix containing a full loading of the pharmacologically active ingredient. The pharmaceutical preparation of the present invention is especially suited for intravaginal placement and the treatment of a condition present therein. When used in the treatment of vaginal afflictions, the pharmaceutical prepa¬ ration of the present invention may be provided in the form of a modified cervical ring adapted for placement around the opening of the cervix. The cervical ring can be loaded with a pharmacologically active ingredient such as clinda- ycin phosphate or trospectomycin sulfate and used in the treatment of bacterial vaginosis. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a perspective view of the pharmaceutical composition of the present invention in the form of a modified cervical ring. -5-

a ounts of more than 20 weight percent of the pharmaceuti¬ cal preparation with the loading level of the pharma¬ cologically active ingredient being based solely on the compatibility of the ingredient with the silicone elastomer matrix.

The plasticizer used in the present invention must be compatible with the silicone elastomer and compatible with the pharmacologically active ingredient to be contained in the silicone elastomer. Typical plasticizers for silicones can be used in the present invention with sorbitol, glycerin and propylene glycol being especially preferred. Of these plasticizers, sorbitol is the most preferred. The plasticizer may be present in the pharmaceutical prepara¬ tion of the present invention in an amount of from about 1 to about 20 percent by weight of the pharmaceutical prepa¬ ration. The amount of the plasticizer can be varied, depending on the pharmacologically active ingredient to be administered and the desired amount and rate of administra¬ tion of the pharmacologically active ingredient into the environment of use.

The pharmaceutical preparation of the present invention additionally contains an osmotic modifier for the silicone elastomer which aids the delivery of the pharmacologically active ingredient from the silicone elastomer into the environment of use. In the present invention, the osmotic modifier is preferably a nontoxic, water-soluble salt, with sodium chloride being especially preferred. Like the plasticizer, the osmotic modifier is preferably contained in the pharmaceutical preparation of the present invention in an amount of from about 1 to about 20 percent by weight based on the total weight of the pharmaceutical prepara¬ tion. The amount of the osmotic modifier contained in the pharmaceutical preparation of the present invention can be -4-

Fig. 2 is a front view of the modified vaginal ring.

Fig. 3 is a sectional view taken along the line III- III in Fig. 2.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical preparation of the present invention contains a pharmacologically active ingredient, a silicone elastomer having the active ingredient contained therein, a plasticizer and an osmotic modifier for the silicone elas¬ tomer. The silicone elastomer used in the present inven- tion can be any medical grade elastomer which is suitable for use as a drug matrix for encapsulating a drug to be administered in a controlled release and which is inert in the environment of use. A particularly preferable silicone elastomer is SILASTIC* MDX 4-4210 medical grade elastomer by Dow Corning. The SILASTIC* MDX 4-4210 medical grade elastomer is an addition-type silicone rubber which con¬ sists of a dimethylsiloxane polymer, a reinforcing silica and a platinum catalyst. The curing agent for the elas¬ tomer consists of a dimethylsiloxane polymer, an inhibitor and a siloxane crosslinker. The elastomer is typically mixed with the curing agent in a ratio of 1 part curing agent per 10 parts by weight of base elastomer.

The pharmacologically active ingredients which can be used in the present invention are not particularly limited and can be chosen according to the condition for which treatment is desired. When used for intravaginal treatment of an affliction such as bacterial vaginosis, the pharma¬ cologically active ingredient used in the present invention is preferably an antibacterial agent such as clindamycin phosphate or trospectomycin sulf te. The amount of the pharmacologically active ingredient loaded into the sili¬ cone elastomer is not limited and may be contained in the pharmaceutical preparation of the present invention in varied depending on the pharmacologically active ingredient to be administered and the desired amount and rate of ad¬ ministration of the pharmacologically active ingredient into the environment of use.

When the present invention is used in the treatment of bacterial vaginosis, it is preferred that the pharma¬ cologically active ingredient be selected from among clin- damycin phosphate and trospectomycin sulfate, the water- soluble plasticizer be sorbitol and the osmotic modifier be sodium chloride. The pharmacologically active ingredient is preferably contained in the pharmaceutical preparation in an amount of from about 10 to about 20 weight percent. The sorbitol plasticizer is contained in the pharmaceutical preparation in an amount of from about 5 to about 15 per¬ cent by weight and the osmotic modifier is preferably contained in the pharmaceutical preparation in an amount of from about 15 to about 20 percent by weight.

When the pharmaceutical preparation of the present invention is used for the treatment of bacterial vaginosis, it is preferably provided in the form of a modified cervi¬ cal ring as shown in Figs. 1-3. As shown in the figures, the modified cervical ring comprises a cylindrical circular annular collar body 11 having an inner flat surface 12 which defines an opening 15 and is adapted to surround and engage with the cervix. A flap member 16 is attached to the annular collar 11 along the circumference thereof at an arc length subtended by a central angle θ of less than 270 degrees. The flap member 16 is of a curved configuration and has a concave surface 17 facing the opening 15. The flap member 16 does not completely cover rhe opening 15 when the inventive pharmaceutical preparation is not used for conception prevention. By having the opening 15 only partially covered, it will be obvious that the modified ring 10 will not.prevent conception by blocking the entrance of the cervix to sperm cells. In the modified cervical ring 10 of the present invention, the pharma¬ cologically active ingredient can be contained only in the flap member 16 or both in the flap member 16 and the annular collar 11.

In use, the modified cervical ring 10 of the present invention is inserted over the cervix such that the concave surface 17 of the flap member 16 is brought into contact with the exterior neck of the cervix. Because of the large surface area of the flap member 16, a larger amount of the pharmacologically active ingredient can be administered directly to the cervix. The surface area of the flap member 16 can be increased or decreased to increase or decrease the total dose delivered.

The present invention is further illustrated in the following examples, but not limited thereby. In the fol¬ lowing examples, parts are given in parts by weight and temperature is in degrees centigrade unless stated other- wise.

Example 1

A master batch of the silicone elastomer base and the curing agent therefor (SILASTIC^# MDX 4-4210 of Dow Corning) were mixed in a weight ratio of 10 parts of elastomer base per one part of curing agent. Ten weight percent of clin- damyc . phosphate, 2 weight percent of sodium chloride and 10 weight percent of sorbitol in powdered form was thoroughly stirred with a portion of the MDX 4-4210 mixture. The formulation was exposed to a vacuum for fifteen minutes to remove entrapped air, formed into a sheet 0.075 ± 0.005 inches thick between two pieces of 3-M low adhesion polyester film, and cured at 100^*C for fifteen minutes. This formulation was then tested by placing a two-inch diameter disk in a standard paddle dissolution apparatus used in determining the in vitro dissolution characteris¬ tics of tablets. The disk was mounted between a three- inch diameter watch glass and a three-inch diameter, 18 mesh stainless steel screen, using the stainless steel wire to secure the screen to the watch glass. The mounted disk was placed screen side up in the dissolution flask, and 300 ml of 0.05 m phosphate buffer having a pH of 7.0 was added, taking care to remove any air entrapped below the formulation. The paddle was lowered sufficiently to be completely submerged in buffer, but not to contact the mounted device. The dissolution apparatus was switched on, and samples taken at intervals. The amount of drug released in three days was determined using standard HPLC methods. The results are shown in Table 1. Example 2

A pharmaceutical preparation according to the present invention was prepared in the exact manner as in Example 1 with the exception that the pharmaceutical preparation contained 5 weight percent of sodium chloride as opposed to 2 percent. This pharmaceutical preparation was tested in the identical manner as in Example 1 and the amount of the drug released from the pharmaceutical preparation was determined after three days. The results are shown in Table 1.

Example 3

A pharmaceutical preparation was prepared in the exact manner as in Examples l and 2 with the exception that the pharmaceutical preparation contained 10 weight percent of sodium chloride. This pharmaceutical preparation was tested for in vitro dissolution in the same manner as in Examples 1 and 2 and the amount of the drug released from the pharmaceutical preparation was determined after three days. The results are shown in Table 1. Example 4

A pharmaceutical preparation according to the present invention was prepared in the exact manner as in Examples

1-3, with the exception that the pharmaceutical preparation contained 20 weight percent of sodium chloride. The in vitro dissolution properties of this pharmaceutical prepa¬ ration was examined in the same manner as in Examples 1-3 and the amount of the drug released from the pharmaceutical preparation was determined after three days. The results are shown in Table 1.

Comparative Example 1

A comparative pharmaceutical preparation was prepared in the same manner as the pharmaceutical preparations of Examples 1-4 with the exception that the pharmaceutical preparation did not contain an osmotic modifier or a plas¬ ticizer. This pharmaceutical preparation was then examined for in vitro drug release in the same manner as in Examples 1-4 and the amount of drug released from the pharmaceutical preparation was determined after three days. The results are shown in Table 1.

Comparative Example 2

A pharmaceutical preparation was made in the same manner as in Examples 1-4 except that the preparation only contained 10 weight percent of sodium chloride in addition to the drug. This pharmaceutical preparation was tested in the same manner as in Examples 1-4 and the amount of drug released in three days was determined. The results are shown in Table 1.

Comparative Example 3

A pharmaceutical preparation was made in the identical manner as shown in Examples 1-4 except that the pharma- ceutical preparation only contained 10 weight percent of sorbitol in addition to the drug. This pharmaceutical preparation was examined for in vitro dissolution proper¬ ties in the same manner as in Examples 1-4 and the amount of drug released into the buffer solution was determined after three days. The results are shown in Table 1.

-11-

TABLE 1

Average Amoun of Drug Re¬

Example leased in Thr No. Additives (% by weight) Days

Example 1 10% Clinda ycin phosphate, 2% NaCl and 10% Sorbitol Example 2 10% Clindamycin phosphate, 5% NaCl and 10% Sorbitol Example 3 10% Clindamycin phosphate, 10% NaCl and 10% Sorbitol Example 4 10% Clindamycin phosphate, 20% NaCl and 10% Sorbitol Com .

As the above data illustrates, use of both a plas¬ ticizer and an osmotic modifier drastically improves the release rate of a drug from a silicone elastomer matrix.

Although a particular preferred embodiment of the invention has been disclosed in detail for illustrative purposes, it will be recognized that variations or modifi cations of the disclosed invention, including the substit tion of equivalents, lie within the scope of the present invention.

Claims

The embodiments of the invention in which an exclusi property or privilege is claimed are defined as follows:

1. A pharmaceutical preparation having improved sus- tained release properties comprising a the.rapeutically effective amount of a pharmacologically active ingredien for treatment of an affliction, a silicone elastomer hav said active ingredient contained therein, a plasticizer said silicone elastomer and an osmotic modifier for said ° silicone elastomer.

2. The pharmaceutical preparation of Claim 1, wherein said plasticizer is water-soluble.

3. The pharmaceutical preparation of Claim 2, wherein said water-soluble plasticizer is one or more members selected from the group consisting of sorbitol, glycerin and propylene glycol.

4. The pharmaceutical preparation of Claim 1, wherein said pharmacologically active ingredient is selected from the group consisting of clindamycin phosphate and trospec- tomycin sulfate.

5. The pharmaceutical preparation of Claim 1, wherein said osmotic modifier is a water-soluble salt.

6. The pharmaceutical preparation of Claim 5, wherein said water-soluble salt is sodium chloride.

7. The pharmaceutical preparation of Claim 1, wherei said pharmacologically active ingredient is contained in said silicone elastomer in an amount of from about 1-20 percent by weight based on the weight of the pharmaceutic preparation.

8. The pharmaceutical preparation of Claim 1, wherein said osmotic modifier is present in said silicone elastom in an amount of from about 1-20 percent by weight based o the weight of the pharmaceutical preparation.

9. The pharmaceutical preparation of Claim 1, wherein said plasticizer is contained in said silicone elastomer an amount of from about 1-20 percent by weight based on t weight of the pharmaceutical preparation.

10. The pharmaceutical preparation of Claim l, wherei said pharmacologically active ingredient is selected from the group consisting of clindamycin phosphate and trospec tomycin sulfate and is contained in said silicone elastom in an amount of about 20 percent by weight, said plas¬ ticizer is sorbitol and is contained in said silicone elastomer in an amount of about 10 percent by weight and said osmotic modifier is sodium chloride and is contained in said silicone elastomer in an amount of about 20 percen by weight, said percent by weight being based on the weigh of the pharmaceutical preparation.

11. A medicinal device for insertion into a vaginal cavity and the sustained administration of a pharmaco¬ logically active ingredient therein, said device comprisin a therapeutically effective amount of a pharmacologically active ingredient for treatment of a vaginal affliction, a silicone elastomer having said active ingredient contain therein, a plasticizer for said silicone elastomer and a osmotic modifier for said silicone elastomer.

12. The medicinal device of Claim 11, wherein said pharmacologically active ingredient is selected from the group consisting of clindamycin phosphate and trospec- tomycin sulfate, said plasticizer is one or more members selected from the group consisting of sorbitol, glycerin and propylene glycol and said osmotic modifier is sodium chloride.

13. The medicinal device of Claim 11, wherein said device comprises an annular collar enclosing an opening f surrounding and engaging with a body part contained withi said vaginal cavity and a flap member attached at an end thereof to said annular collar in such a manner that a portion of said opening is covered by said flap member.

14. The medicinal device of Claim 13, wherein said fl member has a concave surface facing said opening and is attached to said annular collar along the circumference o said annular collar at an arc length subtended by a centr angle of less than 270 degrees.

15. The medicinal device of Claim 13, wherein said bod part is the cervix.

16. The medicinal device of Claim 13, wherein said pharmacologically active ingredient is contained only in said flap member.

17. The medicinal device of Claim 13, wherein said pharmacologically active ingredient is contained both in said annular collar and said flap member.

18. In a method of treating bacterial vaginosis, the improvement comprising utilizing the medical device of Claim 12.