EP1140084A1 - Nouvelle formulation - Google Patents

Nouvelle formulation

Info

Publication number
EP1140084A1
EP1140084A1 EP99959252A EP99959252A EP1140084A1 EP 1140084 A1 EP1140084 A1 EP 1140084A1 EP 99959252 A EP99959252 A EP 99959252A EP 99959252 A EP99959252 A EP 99959252A EP 1140084 A1 EP1140084 A1 EP 1140084A1
Authority
EP
European Patent Office
Prior art keywords
formulation
previous
formulation according
disorders
dibenzo
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99959252A
Other languages
German (de)
English (en)
Inventor
Tina Meinertz Andersen
Thyge Borup Hjorth
Kim Westi Jorgensen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1140084A1 publication Critical patent/EP1140084A1/fr
Withdrawn legal-status Critical Current

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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a novel formulation containing (R)-1-(3-(10,11-Dihydro-5H- dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof, and to its use in the treatment and/or prophylaxis of certain disorders.
  • WO 95/18793 and WO 97/22338 discloses inter alia (R)-1-(3-(10,11-Dihydro-5H- dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof, and the use of the compound to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation.
  • (R)-1- (3-(10, 11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1 -propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof is useful in reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin.
  • formulations containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)- 1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof, as suggested in WO 95/18793 and WO 97/22338, relates to formulations which may be prepared by conventional techniques.
  • the formulations mentioned may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • the half-life for (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3- piperidinecarboxylic acid is relatively short, and in order to control the release of the com- pound in such a manner that an effective concentration in the blood can be maintained over an extended period of time but also that the drug concentration in the blood remains relatively constant over an extended period of time, there exists a need for a modified release formulation for (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yiidene)-1-propyl)-3- piperidinecarboxylic acid.
  • the use of modified release formulations will furthermore improve patient compliance as it reduces the numbers of dosages per day to be taken.
  • one object of the invention is to provide modified release formulations containing (R)-1- (3-(10, 11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1 -propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof in order to reduce the fluctuations in plasma concentrations and thereby reduce any inconvenience hereof.
  • modified release formulations with zero-order drug release.
  • zero-order drug release is difficult to obtain for modified release products, especially for matrix tablets comprising hydroxypropylmethylcellu- lose, which is an often used polymer within modified release formulations.
  • modified release formulations with zero-order drug release containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)- 3-piperidinecarboxyiic acid or a pharmaceutically acceptable salt thereof dispersed in a polymeric matrix comprising at least one release rate controlling polymer can be provided.
  • the present invention further provide modified release formulations with zero-order drug release wherein the polymeric matrix comprises a combination of a polyethylene oxide and a hydroxypropylmethylcellulose so that the in vitro dissolution rate is decreased compared to what is obtained with polyethylene oxide as rate controlling polymer.
  • modified release formulations comprising a combination of a polyethylene oxide and a hydroxypropylmethylcellulose making the in vitro zero-order dissolution profile independent of pH, indicating that the in vivo absorption also is zero-order and independent of pH.
  • the requirements of the dissolution profile for the formulation depends on the disorders to be treated and thereby by the ratio between the polymers used. For disorders having a relatively short treatment period, for example during the night, the dissolution rate should be higher than for disorders requiring once daily treatment.
  • the in vitro dissolution profiles can be modified according to the actual requirement.
  • the present invention further provides a method of treating conditions or indications related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis; urinary incontinence; angiogenesis as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g.
  • NIDDM non-insulin-dependent diabetes mellitus
  • a modified release formulation containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3- piperidinecarboxylic acid or a pharmaceutically compound thereof to a patient in need thereof.
  • the present invention also provides the use of a modified release formulation containing (R)-1 -(3-(10, 11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1 -propyl)-3- piperidinecarboxylic acid or a pharmaceutically compound thereof in the manufacture of a medicament, for treating the above mentioned conditions or indications.
  • the present invention also provides a pharmaceutical composition for use in the treatment of the above mentioned conditions or indications which comprises a modified release formulation containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3- piperidinecarboxylic acid or a pharmaceutically compound thereof.
  • the present invention relates to a modified release formulation with zero-order drug release containing (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1- propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof dispersed in a polymeric matrix comprising at least one release rate controlling polymer.
  • (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)- 1-propyl)-3-piperidinecarboxylic acid may optionally exist as a pharmaceutically acceptable acid addition salt, metal salt or, optionally alkylated, ammonium salt.
  • salts include inorganic and organic acid addition salts such as hydrochlo- ride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tar- trate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
  • (R)-1 -(3-(10, 11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1 -propyl)-3- piperidinecarboxylic acid may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt.
  • Such salt forms exhibit approximately the same order of activity as the free base forms.
  • (R)-1-(3-(10,11-Dihydro-5H- dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid is in the form of the hydrochloride salt.
  • (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3- piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof may be prepared according to the procedures generally outlined in WO 95/18793 and WO 97/22338.
  • modified release is meant any formulation having prolonged, extended or delayed release.
  • modified release formulations which are suitable for incorporating (R)-1-(3- (10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid are described in Hui, H.W., Robinson, J.R. and Lee, V.H.L., Design and Fabrication of Oral Controlled Release Drug Delivery Systems, Controlled Drug Delivery, Fundamentals and Applications, Sec. Ed. edited by J.R. Robinson and V.H.L. Lee 373-432 1987.
  • release rate controlling polymer includes hydrophilic polymers, hydrophobic polymers or mixtures of hydrophilic and/or hydrophobic polymers that are capable of retarding the release of (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5- ylidene)-1-propyl)-3-piperidinecarboxylic acid in vivo when the compound is dispersed in a polymeric matrix formed from the release rate controlling polymers.
  • release rate controlling polymers to be used in this invention include hydroxyal- kylcellulose, such as hydroxypropylmethylcellulose and hydroxypropylcellulose; polyethylene oxide; alkylcellulose such as ethylcellulose and methylcellulose; carboxymethylcellulose; hy- drophilic cellulose derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvi- nylacetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; polyalkyl methacrylate; and polyvinyl acetate.
  • Other suitable hydrophobic polymers include polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac and hydrogenated vegetable oils.
  • the release rate controlling polymers include a hydroxypropylmethylcellulose, a polyethylene oxide, or a combination thereof.
  • a release formulation containing a polyethylene oxide In a particular embodiment of the invention there is provided a release formulation containing a polyethylene oxide.
  • a release formulation containing a hydroxypropylmethylcellulose and a polyethylene oxide.
  • hydroxypropylmethylcellulose for use in accordance with the invention is an hydroxypropylmethylcellulose sold under the trademark Methocel (Dow Chemical Co.) or equivalents.
  • Suitable Methocels include the K grades such as Methocel K15M Premium CR, Methocel K100M Premium CR, Methocel K100 Premium LV and Methocel K4M Premium.
  • Other suitable Methocels include the E, F and J grades.
  • Suitable Polyoxs include the Polyox WSR grades such as Polyox WSR Coagulant, Polyox WSR-301 , Polyox WSR-303, Polyox WSR-1105.
  • the hydroxypropylmethylcelluloses used according to the invention preferably have a viscos- ity (2 wt% solution at 20 °C) of about 100 to 100,000 cps. Especially suitable are Methocel K types or their equivalents.
  • the polyethylene oxide used according to the invention preferably has a molecular weight of about 100,000 to 7,000,000, more preferably 900,000 to 7,000,000.
  • the formulation of the present invention contains about 5 and 75% by weight, preferably about 20 and 50% by weight release rate controlling poly ⁇
  • the modified release formulations according to the present invention may preferably include any relevant filler.
  • the choice of these excipients and their quantity may easily be determined by a person skilled in the art.
  • the exicipients includes diluents, various binders, disin- tegrants, lubricants, colorants, sweeteners and the like.
  • Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • examples of diluents include microcrystalline cellulose such as Avicel pH112,
  • Avicel pH101 and Avicel pH102 lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL 21 ; dibasic calcium phosphate such as Emcompress; mannitol; starch; sorbitol; sucrose and glucose.
  • Suitable lubricants include, for example, colloidal silicon dioxide such as Aerosil 200; talc; stearic acid; magnesium stearate and calcium stearate.
  • Suitable binders include polyethylene glycols such as PEG 6000; cetostearyl alcohol; cetyl alcohol; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates; polyoxamers and waxes.
  • the modified release formulation can be produced either by using a granulation method followed by compression or by direct compression, thereby avoiding the granulation process step.
  • Preferred formulations of the modified release formulations are ultimately enteric coated tablets or capsules, wax or polymer coated tablets or capsules or time-release matrices, or combinations thereof. Particular preferred formulations are matrix tablets.
  • (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3- piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof in the form of a modified release formulation can be used in the treatment of conditions or indications related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, e.g.
  • acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post-herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post- traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, itching, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
  • the present compound in the form of a modified release formulation may also be used in the treatment of conditions or indications related to urinary incontinence or angiogenesis.
  • (R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3- piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof in the form of a modified release formulation can be used in the treatment of conditions or indications caused by or related to the secretion and circulation of insulin antagonising peptides and other peptides derived from the sensory nervous system, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • treatment as used herein may be described as the treatment, prevention, elimination, alleviation or amelioration of one of the above disorders.
  • patient as used herein includes any mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of the above disorders.
  • mammals include also animals, both domestic animals, e.g. household pets, and non- domestic animals such as wildlife.
  • zero-order drug release and “first-order drug release” as used herein refer to an in vitro zero-order drug release and an in vitro first-order drug release respectively.
  • Sentry Polyox WSR 1105 When using high molecular weight polyethylene oxide, Sentry Polyox WSR 1105, in concentrations of 48 or 60%, zero-order dissolution profiles occur. The dissolution rate decreases as the content of matrix polymer increases.
  • hydroxypropymethylcelluloses as matrix polymers causes first-order dissolution profiles (Example 1), when combining the hydroxypropylmethylcellulose, Methocel K100M Premium CR, and the high molecular weight polyethylene oxide, Sentry Polyox WSR 1105, zero-order dissolution profiles are obtained. Even with 24% high molecular weight polyethylene oxide and 36% hydroxypropylmethylcellulose, zero-order dissolution profiles are obtained.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Medicinal Preparation (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Une formulation à libération modifiée contient de l'acide (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptèn-5-ylidène)-1-propyl)-3-pipéridinecarboxylique ou un composé pharmaceutique de celui-ci.
EP99959252A 1998-12-22 1999-12-14 Nouvelle formulation Withdrawn EP1140084A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK170398 1998-12-22
DKPA199801703 1998-12-22
PCT/DK1999/000699 WO2000037081A1 (fr) 1998-12-22 1999-12-14 Nouvelle formulation

Publications (1)

Publication Number Publication Date
EP1140084A1 true EP1140084A1 (fr) 2001-10-10

Family

ID=8107354

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99959252A Withdrawn EP1140084A1 (fr) 1998-12-22 1999-12-14 Nouvelle formulation

Country Status (4)

Country Link
EP (1) EP1140084A1 (fr)
JP (1) JP2002532551A (fr)
AU (1) AU1649700A (fr)
WO (1) WO2000037081A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6723340B2 (en) * 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
MY152185A (en) * 2005-06-10 2014-08-29 Novartis Ag Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation
CN114533699B (zh) * 2021-12-15 2023-05-26 南通联亚药业股份有限公司 一种盐酸环苯扎林缓释胶囊及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4680323A (en) * 1983-12-01 1987-07-14 Hans Lowey Method and composition for the preparation of controlled long-acting pharmaceuticals for oral administration
MY113463A (en) * 1994-01-04 2002-03-30 Novo Nordisk As Novel heterocyclic compounds
IL124557A0 (en) * 1995-12-15 1998-12-06 Novo Nordisk As Compositions for reducing blood glucose and/or inhibiting the activity of cgrp
US5783212A (en) * 1996-02-02 1998-07-21 Temple University--of the Commonwealth System of Higher Education Controlled release drug delivery system

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0037081A1 *

Also Published As

Publication number Publication date
AU1649700A (en) 2000-07-12
JP2002532551A (ja) 2002-10-02
WO2000037081A1 (fr) 2000-06-29

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