+

WO1996012476A1 - Formulation pour granulation par voie humide d'un antagoniste du recepteur de la piperazinylcamphorsulfonyl oxytocine - Google Patents

Formulation pour granulation par voie humide d'un antagoniste du recepteur de la piperazinylcamphorsulfonyl oxytocine Download PDF

Info

Publication number
WO1996012476A1
WO1996012476A1 PCT/US1995/013342 US9513342W WO9612476A1 WO 1996012476 A1 WO1996012476 A1 WO 1996012476A1 US 9513342 W US9513342 W US 9513342W WO 9612476 A1 WO9612476 A1 WO 9612476A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
active ingredient
granules
tablet
pvp
Prior art date
Application number
PCT/US1995/013342
Other languages
English (en)
Inventor
Mandana Asgharnejad
David E. Storey
Original Assignee
Merck & Co., Inc.
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 Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU38342/95A priority Critical patent/AU3834295A/en
Publication of WO1996012476A1 publication Critical patent/WO1996012476A1/fr

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

Definitions

  • the present invention relates to solid dosage formulations and process for manufacture of an oxytocin receptor antagonist. More specifically, the invention relates to a wet granulation formulation of the oxytocin receptor antagonist compound.
  • wet granulation is one of the more prevalent methods.
  • approximately 20 to 30% of the tablet weight comprises active ingredient and 70 to 80% comprises excipients (i.e., inert ingredients, additives).
  • Piperazinylcamphorsulphonyl oxytocin receptor antagonists have been disclosed as being useful in the treatment of oxytocin-related conditions such as preterm labor, dysmenorrhea and stopping labor prior to cesarean delivery. These oxytocin receptor antagonist compounds and their utility in treating oxytocin-related disorders are described in EP Patent Publication No. 532,097, published 17 March 1993.
  • Example 36 of EP 532,097 i.e., 1 -((7,7-Dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)- butyramido)bicyclo(2.2.1 )heptan- 1 -yl)methanesulfonyl)-4-(2- methylphenyl)piperazine, is a potent, orally active oxytocin antagonist useful in the treatment of preterm labor and will hereafter be referred to as Compound A.
  • Preferred crystalline salts of Compound A are disclosed in EP Patent Publication Number 614,894, published 14 September 1994 and PCT International Application No. WO94/20483, published 15 September 1994.
  • Standard methods for tablet formulation of Compound A suffer difficulties. Because of the bulk of the active ingredient, i.e., Compound A, or a pharmaceutically acceptable salt thereof, and the high dose required to effectively treat the oxytocin-related conditions previously described, numerous problems in formulating a stable, robust tablet occurred. In the 600 mg dosage, almost 80% of the tablet weight is active ingredient and only about 20% of the tablet weight is excipients. This is contrasted with a typical solid formulation wherein the opposite is true, i.e., about 20% is active ingredient and 80% is excipients. Thus, standard methods of preparing a stable solid formulation of Compound A were unsuccessful.
  • the present invention now provides a wet granulated formulation of Compound A and process therefore wherein the tablet formulation is stable and robust.
  • the present invention provides a process for the preparation of a tablet containing an active ingredient of l-((7,7- Dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)butyramido)- bicyclo(2.2.1 )heptan-l -yl)methanesulfonyl)-4-(2-methylphenyl)- piperazine, or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • the tablet contains about 23 to 80% by weight of the active ingredient, preferably about 70 to 80% by weight of the active ingredient.
  • the active ingredient is 1- ((7,7-Dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)butyramido)- bicyclo(2.2.1 )heptan- 1 -yl)methanesulfonyl)-4-(2-methy Iphenyl)- piperazine hemisulfate salt.
  • Illustrative of the invention is the process wherein coating the tablet is accomplished by:
  • An illustration of the invention is the process wherein the tablet contains about 23 to 80% by weight of the active ingredient, preferably about 70 to 80% by weight of the active ingredient.
  • the active ingredient is l -((7,7-Dimethyl-2-endo-(2S-amino-4- (methy lsulfonyl)butyramido)bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine hemisulfate salt.
  • the diluent is microcrystalline cellulose
  • the first and second binders are selected from pregelatinized starch or PVP
  • the disintegrant is croscarmellose sodium
  • the lubricant is magnesium stearate.
  • the first binder is pregelatinized starch and the second binder is PVP.
  • An example of the invention is the process further comprising the step of applying a coating to the tablet.
  • a further illustration of the invention is the process wherein the tablet contains about 23 to 80% by weight of the active ingredient, preferably about 70 to 80% by weight of the active ingredient.
  • Another example of the invention is the process wherein the active ingredient is l -((7,7-Dimethyl-2-endo-(2S-amino-4- (methy lsulfony l)butyramido)bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)piperazine hemisulfate salt.
  • An additional illustration of the invention is a solid dosage form containing an active ingredient of l-((7,7-Dimethyl-2-endo-(2S- amino-4-(methylsulfonyl)butyramido)-bicyclo(2.2.1 )heptan- 1 - yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine, or a pharmaceutically acceptable salt thereof, wherein the dosage form is prepared by the process.
  • Granulation is the process of adding water to a powder mixture until granules are formed.
  • the granulation step may be varied from 2 to 30 minutes, preferably 2 to 10 minutes, most preferably 4 to 8 minutes.
  • the granules are dried using a fluid bed dryer or tray dryer. Milling of the dried granules is accomplished using a Quadro Comill or Fitz mill.
  • the lubrication step is the process of adding lubricant to the mixture; the lubrication step may be varied from 30 seconds to 20 minutes, preferably about 1 minute.
  • the disclosed process may be used to prepare solid dosage forms, particularly tablets, for medicinal administration.
  • tablette is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated. Substances which may be used for coating include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), titanium dioxide, talc, sweeteners and colorants.
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • titanium dioxide titanium dioxide
  • talc titanium dioxide
  • sweeteners and colorants sweeteners and colorants.
  • active ingredient includes both the free base Compound A, as well as the pharmaceutically acceptable salts thereof.
  • Preferred diluents include: lactose, microcrystalline cellulose, calcium phosphate(s), mannitol, powdered cellulose, pregelatinized starch and other suitable diluents (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, p. 1635).
  • Microcrystalline cellulose is particularly preferred. Specifically, microcrystalline cellulose NF, especially Avicel PH101, the trademarked name for microcrystalline cellulose NF manufactured by FMC Corp. is preferred.
  • Preferred binders include pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP) and other known binders (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, pp. 1635- 1636. Most preferably, pregelatinized starch and/or PVP are employed as binders. Specifically, starch pregelatinized NF 1500 manufactured by Colorcon Corporation and PVP 29/33 manufactured by TSP Technologies are most preferred.
  • the disintegrant may be one or more of several starches, clays, celluloses, algins, gums or crosslinked polymers known to those skilled in the art. (See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, p. 1637).
  • one or more of several modified starches or modified cellulose polymers such as microcrystalline cellulose and croscarmellose sodium, are used.
  • Croscarmellose sodium Type A commercially available under the trade name "Ac-di-sol,” is particularly preferred.
  • Preferred lubricants include magnesium stearate, calcium stearate, stearic acid, surface active agents such as sodium lauryl sulfate, propylene glycol, sodium dodecane sulfonate, sodium oleate sulfonate and sodium laurate mixed with stearates and talc, sodium stearyl famerate and other known lubricants (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, 1990, pp. 1636-1637). Especially preferred is magnesium stearate.
  • the active ingredient, Compound A can be prepared according to the methods disclosed in EP Patent Publication No.
  • the pharmaceutically acceptable salts of Compound A may also be employed in the instant invention.
  • examples of pharmaceutically acceptable salts include the sulfate, tartrate, hydrochloride, maleate and phosphate salts.
  • crystalline salts of Compound A are employed.
  • the crystalline sulfate salt, specifically the crystalline hemisulfate salt, is particularly preferred.
  • the salts may be prepared by methods known in the art; the crystalline salts may be prepared according to the methods taught in EP Patent Publication No. 614,894, published 14 September 1994 and PCT International Application No. WO94/20483, published 15 September 1994.
  • compositions of the present invention comprise 23 to 80% by weight of an active ingredient which is
  • Compound A i.e., l-((7,7-Dimethyl-2-endo-(2S-amino-4-(methyl- sulfonyl)butyramido)bicyclo(2.2.1 )heptan- 1 -yl)methanesulfonyl)-4-(2- methylpheny piperazine, or a pharmaceutically acceptable salt thereof; 0 to 77% by weight of a first binder; 0 to 77% by weight of a diluent; 0 to 5% by weight of a second binder; 0 to 6% by weight of a disintegrant; and 0 to 5% by weight of a lubricant.
  • the first and second binders are selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, pregelatinized starch or PVP;
  • the diluent is selected from lactose, microcrystalline cellulose, calcium phosphate, mannitol, powdered cellulose or pregelatinized starch;
  • the disintegrant is selected from microcrystalline or croscarmellose sodium;
  • the lubricant is selected from magnesium stearate, calcium stearate, steric acid or a surface active agent.
  • the first binder is pregelatinized starch; the diluent is microcrystalline cellulose; the second binder is PVP; the disintegrant is croscarmellose sodium; and the lubricant is magnesium stearate.
  • the pharmaceutical compositions of the present invention are preferably in the form of tablets.
  • the tablets may be, for example, from 50 mg to 1.0 g in net weight, preferably 100 to 900 mg net weight, more preferably 200 to 870 mg net weight.
  • Preferred pharmaceutical compositions comprise about 23 to 80% by weight of the active ingredient, about 9 to 27% by weight of pregelatinized starch; about 9 to 51 % by weight of microcrystalline cellulose; about 1 to 5% by weight of PVP 29/32; about 0.5 to 6% by weight of croscarmellose sodium; and about 0.1 to 5% by weight of magnesium stearate.
  • compositions in accordance with the present invention comprise: about 65.2 to 76.71 % by weight of the active ingredient; about 9.39 to 27% by weight of pregelatinized starch; about 9.39 to 27% by weight of microcrystalline cellulose; about 1.0 to 5.0 % by weight of PVP 29/32; about 1.0 to 6% by weight of croscarmellose sodium; and about 0.5 to 5% by weight of magnesium stearate.
  • compositions as envisioned for commercial development are as follows:
  • Tablets of 100 mg potency free base about 23.5% by weight of active ingredient; about 19% by weight of pregelatinized starch; about 50.9% by weight of microcrystalline cellulose; about 2% by weight of PVP 29/32; about 1.5% by weight of croscarmellose sodium; and about 1 % by weight of magnesium stearate.
  • Tablets of 200 mg potency free base about 23.5% by weight of active ingredient; about 19% by weight of pregelatinized starch; about 50.9% by weight of microcrystalline cellulose; about 2% by weight of PVP 29/32; about 1.5% by weight of croscarmellose sodium; and about 1 % by weight of magnesium stearate.
  • Tablets of 600 mg potency free base about 76.71 % by weight of active ingredient; about 9.39% by weight of pregelatinized starch; about 9.39% by weight of microcrystalline cellulose; about 2% by weight of PVP 29/32; about 1.5% by weight croscarmellose sodium; and about 1 % by weight of magnesium stearate.
  • the tablets of the 200 mg potency are preferably formulated in an 850 mg tablet containing 425 ⁇ l purified water per tablet.
  • the 600 mg potency tablets are preferably formulated in an 850 mg tablet containing 510 ⁇ l purified water per tablet.
  • the tablet formulations of the instant invention are coated.
  • the tablets of 200 mg and 600 mg potency free base are coated with about 0.78% by weight of hydroxypropyl methylcellulose; about 0.78% by weight of hydroxypropyl cellulose; about 0.31 % by weight titanium dioxide; and about 0.078% by weight of purified talc.
  • the active ingredient in the above-described pharmaceutical compositions is the hemisulfate salt of Compound A.
  • the pharmaceutical tablet compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients (also referred to as "additives”) known in the pharmaceutical formulation art. According to the desired properties of the tablet, any number of additives may be selected, alone or in combination, based upon their known uses in preparing tablet compositions. Such additives include, but are not limited to, diluents, binders, compression aids, disintegrants, lubricants, flavors, flavor enhancers, sweeteners and preservatives.
  • compositions of the present invention are useful in the therapeutic treatment of oxytocin-related disorders such as preterm labor, dysmenorrhea and stopping labor prior to cesarean delivery.
  • the active ingredient (equivalent to 600 mg anhydrous free base per tablet) was mixed with the starch pregelatinized NF 1000 and microcrystalline cellulose NF in a high Fielder 10/25 mixer for 3 minutes.
  • the PVP 29/32 was dissolved in the water and this solution added to the powder mixture with the mixer running over a period of 1.5 to 3.0 minutes then granulated for 4.5 minutes to form granules.
  • the wet granules were dried at about 47°C (range 46 to 48°C) in a tray dryer for 5.0 hours. The dried granules were then milled using a Quadro Comill to achieve fine granules.
  • croscarmellose sodium NFS disintegrant
  • Magnesium stearate impalpable powder NF lubricant
  • the lubricated mixture was compressed to provide tablets of 600 mg active ingredient (free base equivalent).
  • the titanium dioxide and talc, USP were mixed and passed through a 60 mesh stainless steel screen. This mixture was mixed with HPMC and HPC to form a dry blend.
  • the dry blend was added to water (147 ml) which was previously heated to 90°C with mild agitation to ensure that the blend is wetted to form a slurry.
  • the remainder of the water (up to 442.0 ml) was added to the slurry at ambient temperature with gentle agitation to form a suspension.
  • the suspension was then applied to the tablets from Example 1 using the following guidelines to provide the coated tablets.
  • the active ingredient (equivalent to 200 mg anhydrous free base per table) was mixed with starch pregelatinized NF 1500 and microcrystalline cellulose NF in a Fielder mixer at slow speed for 5 minutes, then at fast speed for 2 more minutes.
  • PVP 29/32 was dissolved in water and the resulting solution added to the powder mixture in the fielder with the mixture running over a period of 3 to 5 minutes, then granulating for 8 minutes to form granules.
  • the wet granules were dried at about 47°C (range 46-48°C) for 8.63 hours. The dried granules were then milled using a Quadro Comill to achieve fine granules.
  • croscarmellose sodium NF disintegrant
  • croscarmellose sodium NF disintegrant
  • Magnesium stearate impalpable powder NF lubricant
  • the lubricated mixture was compressed to provide tablets of 200 mg active ingredient (free base equivalent).
  • Example 2 Using essentially the procedure of Example 2 and applying the suspension to the tablets from Example 3, 200 mg potency coated tablets were formed.

Landscapes

  • Health & Medical Sciences (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)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un comprimé dont le principe actif est un antagoniste de récepteur d'oxytocine. Le comprimé se prépare en formant un mélange pulvérulent comprenant, d'une part d'un principe actif constitué par la 1-(7,7-diméthyl)-2-endo-2S-amino-4-(méthylsulfonyl)-butyramido)bicyclo(2.2.1)heptane-1-yl)méthanesulfonyl)-4-(2-méthylphényl)pipérazine, ou l'un de ses sels acceptables du point de vue pharmaceutique, et d'autre part un premier liant et un diluant. Le procédé consiste ensuite à réaliser la granulation par voie humide du mélange pulvérulent avec une solution d'un second liant dans l'eau jusqu'à constituer des granules. Le procédé consiste enfin à sécher les granules pour en éliminer l'eau, puis à compresser les granules pour leur donner la forme voulue du comprimé.
PCT/US1995/013342 1994-10-20 1995-10-16 Formulation pour granulation par voie humide d'un antagoniste du recepteur de la piperazinylcamphorsulfonyl oxytocine WO1996012476A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38342/95A AU3834295A (en) 1994-10-20 1995-10-16 Wet granulation formulation for a piperazinylcamphorsulfonyl oxytocin receptor antagonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32641894A 1994-10-20 1994-10-20
US326,418 1994-10-20

Publications (1)

Publication Number Publication Date
WO1996012476A1 true WO1996012476A1 (fr) 1996-05-02

Family

ID=23272115

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/013342 WO1996012476A1 (fr) 1994-10-20 1995-10-16 Formulation pour granulation par voie humide d'un antagoniste du recepteur de la piperazinylcamphorsulfonyl oxytocine

Country Status (2)

Country Link
AU (1) AU3834295A (fr)
WO (1) WO1996012476A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806359A (en) * 1987-04-22 1989-02-21 Mcneilab, Inc. Iburprofen sustained release matrix and process
US5073380A (en) * 1987-07-27 1991-12-17 Mcneil-Ppc, Inc. Oral sustained release pharmaceutical formulation and process
EP0532097A1 (fr) * 1991-09-13 1993-03-17 Merck & Co. Inc. Pipérazinyl(sulfon)amides dérivés du camphre comme agents antagonistes de l'oxytocine
EP0614894A1 (fr) * 1993-03-12 1994-09-14 Merck & Co. Inc. Procédé pour la préparation de dérivés d'amines substitués de pipérazinylcamphorsulphonyl oxytocin antagonistes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806359A (en) * 1987-04-22 1989-02-21 Mcneilab, Inc. Iburprofen sustained release matrix and process
US5073380A (en) * 1987-07-27 1991-12-17 Mcneil-Ppc, Inc. Oral sustained release pharmaceutical formulation and process
EP0532097A1 (fr) * 1991-09-13 1993-03-17 Merck & Co. Inc. Pipérazinyl(sulfon)amides dérivés du camphre comme agents antagonistes de l'oxytocine
EP0614894A1 (fr) * 1993-03-12 1994-09-14 Merck & Co. Inc. Procédé pour la préparation de dérivés d'amines substitués de pipérazinylcamphorsulphonyl oxytocin antagonistes

Also Published As

Publication number Publication date
AU3834295A (en) 1996-05-15

Similar Documents

Publication Publication Date Title
KR100348842B1 (ko) 염기성물질로안정화된약제학적조성물
KR100554816B1 (ko) 비결정질 넬피나비르 메실레이트의 약학 제형
EP1468679B1 (fr) Composition de tramadol à libération contrôlée
JP4172820B2 (ja) 速溶性臭化水素酸ガランタミン錠剤
EP0305051B1 (fr) Formulation orale d'acétaminophène avec libération étalée et procédé pour la préparer
EP0274845B1 (fr) Compositions pharmaceutiques solides et stables contenant de l'ibuprofène et de la codéine
TWI228414B (en) Pharmaceutical composition comprising carvedilol and hydrochlorothiazide, solid dosage form comprising it, and process for the production of the same
KR100202154B1 (ko) 파라세타몰 및 돔페리돈을 함유한 필름 피복 정제
EP0503440A1 (fr) Compositions à base de sumatriptan
EA004311B1 (ru) Таблетированная фармацевтическая композиция непролонгированного действия
EP1266657A1 (fr) Compositions pharmaceutiques d'hydrochlorure de bupropion, stabilisées par la cyclodextrine
AU757547B2 (en) Novel compositions of eprosartan
JP3586471B2 (ja) トラセミド含有医薬組成物
JP2002532429A (ja) 薬学的処方物
JP3836893B2 (ja) ポリカルボフィルカルシウム含有製剤
TWI356711B (en) Saquinavir mesylate oral dosage form
EP0379579A1 (fr) Preparation pharmaceutique a liberation amelioree
EP0266707B1 (fr) Comprimé de labetalol à libération prolongée
AU756338B2 (en) Stabile compositions comprising levosimendan and alginic acid
US4940580A (en) Sustained release labetalol tablets
WO1996012476A1 (fr) Formulation pour granulation par voie humide d'un antagoniste du recepteur de la piperazinylcamphorsulfonyl oxytocine
CA2462275A1 (fr) Nouvelle composition de carvedilol
JPH08325142A (ja) ヨウ化イソプロパミド含有製剤
CA2499149A1 (fr) Formulation de mannitol destinee a un antagoniste de recepteur d'integrine
CA1209046A (fr) Composes diuretiques/antihypertenseurs et methode de preparation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU BB BG BR BY CA CN CZ EE FI GE HU IS JP KG KR KZ LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM TT UA US UZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载