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WO1992018101A1 - Dispositif d'administration vaginale de substances medicamenteuses - Google Patents

Dispositif d'administration vaginale de substances medicamenteuses Download PDF

Info

Publication number
WO1992018101A1
WO1992018101A1 PCT/US1992/002659 US9202659W WO9218101A1 WO 1992018101 A1 WO1992018101 A1 WO 1992018101A1 US 9202659 W US9202659 W US 9202659W WO 9218101 A1 WO9218101 A1 WO 9218101A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical preparation
active ingredient
silicone elastomer
contained
pharmacologically active
Prior art date
Application number
PCT/US1992/002659
Other languages
English (en)
Inventor
David Wade Osborne
Carolyn V. Pesheck
Original Assignee
The Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Publication of WO1992018101A1 publication Critical patent/WO1992018101A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms

Definitions

  • compositions 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention relates to an improved pharma ⁇ ceutical preparation
  • a silicone elastomer matrix 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.
  • 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.
  • a pharmacologically active ingredient such as clinda- ycin phosphate or trospectomycin sulfate
  • Fig. 1 is a perspective view of the pharmaceutical composition of the present invention in the form of a modified cervical ring. -5-
  • 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.
  • the osmotic modifier is preferably a nontoxic, water-soluble salt, with sodium chloride being especially preferred.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ 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.
  • the modified ring 10 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Préparation pharmaceutique à libération prolongée améliorée composée d'une matrice en élastomère au silicone contenant un ingrédient pharmacologiquement actif, un plastifiant et un modificateur osmotique pour l'élastomère au silicone. Ladite préparation pharmaceutique peut être fournie sous forme d'un dispositif médical à insérer dans une cavité vaginale afin d'administrer l'ingrédient pharmacologiquement actif dans ladite cavité. Le dispositif médical peut également être fourni sous forme d'un anneau circulaire modifié qui entoure une partie corporelle présente au sein de la cavité vaginale et s'adapte sur elle. Un volet est attaché par une de ses extrémités à l'anneau circulaire de telle manière qu'une partie de l'ouverture définie par la bague annulaire est recouverte par le volet. Ladite préparation pharmaceutique convient particulièrement au traitement de la vaginite bactérienne.
PCT/US1992/002659 1991-04-12 1992-04-08 Dispositif d'administration vaginale de substances medicamenteuses WO1992018101A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68508891A 1991-04-12 1991-04-12
US685,088 1991-04-12

Publications (1)

Publication Number Publication Date
WO1992018101A1 true WO1992018101A1 (fr) 1992-10-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/002659 WO1992018101A1 (fr) 1991-04-12 1992-04-08 Dispositif d'administration vaginale de substances medicamenteuses

Country Status (2)

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AU (1) AU1797592A (fr)
WO (1) WO1992018101A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0664120A1 (fr) * 1993-12-23 1995-07-26 Roussel Uclaf Dispositif pour l'administration ragimale du tamoxifème et de ses analogues
EP0667161A1 (fr) * 1994-02-09 1995-08-16 MERCK PATENT GmbH Formes dosées à libération retardée contenant de la clindamycine oalmitate
WO2002076426A3 (fr) * 2001-03-27 2003-04-17 Galen Chemicals Ltd Dispositifs d'administration de medicament par voie intravaginale destines a l'administration d'agent antimicrobien
EP1301150A4 (fr) * 2000-07-11 2004-08-11 Umd Inc Dispositif et methode de traitement intravaginal ou transvaginal d'infections fongiques, bacteriennes, virales ou parasitaires
JP2007536299A (ja) * 2004-05-04 2007-12-13 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｔｂ４アンタゴニトを含有する固形医薬形態
US9789057B2 (en) 2003-09-19 2017-10-17 Perrigo Pharma International Designated Activity Company Pharmaceutical delivery system

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4177256A (en) * 1973-04-25 1979-12-04 Alza Corporation Osmotic bursting drug delivery device
EP0050867A1 (fr) * 1980-10-28 1982-05-05 Schering Aktiengesellschaft Vaginalring
WO1989004682A1 (fr) * 1987-11-23 1989-06-01 Colorado Biomedical Incorporated Procede et dispositif anti-microbiens

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4177256A (en) * 1973-04-25 1979-12-04 Alza Corporation Osmotic bursting drug delivery device
EP0050867A1 (fr) * 1980-10-28 1982-05-05 Schering Aktiengesellschaft Vaginalring
WO1989004682A1 (fr) * 1987-11-23 1989-06-01 Colorado Biomedical Incorporated Procede et dispositif anti-microbiens

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Drug Development and Industrial Pharmacy, vol. 11, nos. 6,7, November 1985, D.S.T HSIEH et al.: "Enhanced release of drugs from silicone elastomers release kinetics of pineal and steroidal hormones", pages 1391-1410, see the whole document *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0664120A1 (fr) * 1993-12-23 1995-07-26 Roussel Uclaf Dispositif pour l'administration ragimale du tamoxifème et de ses analogues
EP0667161A1 (fr) * 1994-02-09 1995-08-16 MERCK PATENT GmbH Formes dosées à libération retardée contenant de la clindamycine oalmitate
EP1301150A4 (fr) * 2000-07-11 2004-08-11 Umd Inc Dispositif et methode de traitement intravaginal ou transvaginal d'infections fongiques, bacteriennes, virales ou parasitaires
WO2002076426A3 (fr) * 2001-03-27 2003-04-17 Galen Chemicals Ltd Dispositifs d'administration de medicament par voie intravaginale destines a l'administration d'agent antimicrobien
JP2004524343A (ja) * 2001-03-27 2004-08-12 ガレン（ケミカルズ）リミティド 抗菌剤投与のための膣内用ドラッグデリバリーデバイス
US6951654B2 (en) * 2001-03-27 2005-10-04 Galen (Chemicals) Limited Intravaginal drug delivery devices for the administration of an antimicrobial agent
JP2011236243A (ja) * 2001-03-27 2011-11-24 Warner Chilcott (Ireland) Ltd 抗菌剤投与のための膣内用ドラッグデリバリーデバイス
US9789057B2 (en) 2003-09-19 2017-10-17 Perrigo Pharma International Designated Activity Company Pharmaceutical delivery system
JP2007536299A (ja) * 2004-05-04 2007-12-13 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｌｔｂ４アンタゴニトを含有する固形医薬形態

Also Published As

Publication number Publication date
AU1797592A (en) 1992-11-17

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