WO1997004795A2 - Compositions pharmaceutiques contenant de la cyclosporine et d'autres substances peptidiques - Google Patents

Compositions pharmaceutiques contenant de la cyclosporine et d'autres substances peptidiques Download PDF

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Publication number
WO1997004795A2
WO1997004795A2 PCT/GB1996/001772 GB9601772W WO9704795A2 WO 1997004795 A2 WO1997004795 A2 WO 1997004795A2 GB 9601772 W GB9601772 W GB 9601772W WO 9704795 A2 WO9704795 A2 WO 9704795A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical preparation
preparation according
group
cyclosporin
component
Prior art date
Application number
PCT/GB1996/001772
Other languages
English (en)
Other versions
WO1997004795A3 (fr
Inventor
Stefano Poli
Cesare Busetti
Tiziano Crimella
Vincenzo Olgiati
Original Assignee
Poli Industria Chimica S.P.A.
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 Poli Industria Chimica S.P.A. filed Critical Poli Industria Chimica S.P.A.
Priority to AU65285/96A priority Critical patent/AU6528596A/en
Publication of WO1997004795A2 publication Critical patent/WO1997004795A2/fr
Publication of WO1997004795A3 publication Critical patent/WO1997004795A3/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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to pharmaceutical preparations containing peptide substances.
  • Peptide substances are usually administered in the form of aqueous solutions or dispersions, or in at least partially aqueous solutions or dispersions, since they exhibit greater bio-compatibility.
  • compositions in combination with pharmaceutically-active ingredient.
  • the compositions lead to quantitatively variable absorption profiles of the active ingredient, particularly with respect to a cyclosporin.
  • compositions consisting of one or more of the following components: a non-ionic ester of a triglyceride and of a polyalkylene-polyol, a triglyceride of saturated fatty acids and a monoglyceride.
  • GB Patent No. 2,221,157 proposes a mixture of a saturated fatty hydroxyacid monoester with polyethylene glycol and one or more mono- or poly-hydroxyl alcohols as the carrier.
  • German Patent No. 4003844 proposes a carrier comprising a fatty acid saccharide ester in addition with a specific solvent or with a polyalkylene glycol having a molecular weight greater than 7,000.
  • GB Patent No. 2,278,780 proposes at least one ternary carrier consisting of a surfactant which is the transesterification product of a vegetable oil and mono-, di- or tri-glycerides of oleic and/or linoleic and/or of polyoxyethylated vegetable oil, along with propylene glycol and ethanol.
  • GB Patent No. 2,218,334 proposes, for the topical use, the dispersion of an active ingredient in fixed ratios in a C 12 -C 24 mono- or poly-unsaturated alcohol or acid, addition to other optional excipients.
  • US Patent No. 5,342,625 proposes a composition which attains a more homogeneous adso ⁇ tion of the active ingredient by means of a formulation consisting in the preconcentrate of an surfactant-free microemulsion.
  • GB Patent No. 2228198 proposes a carrier consisting of a fatty acid triglyceride, a partial ester of fatty acids with glycerol or propylene glycol or sorbitol, a surfactant with an HLB greater than 10.
  • GB Patent No. 2257359 proposes a composition comprising an alkylene glycol, a surfactant and a mixture of C 12 -C 20 fatty acid mono-, di- and tri- glycerides.
  • GB Patent No. 2270842 proposes a microemulsion preconcentrate containing a hydrophilic organic solvent combined with mixed mono-, di- or tri- glycerides or transesterified and polyoxyethylated vegetable oil, in the presence of a surfactant, namely polyoxyethylated fatty acid ester sorbitan.
  • the present invention provides a pharmaceutical preparation comprising (a) a peptide substance; (b) at least one component selected from the group consisting of a polyoxyalkyl, a vinyl polymer, an acrylic polymer, linear polymers thereof, and crosslinked copolymers thereof; and (c) at least one component selected from the group consisting of monmoesters of fatty acids containing alcohols wherein each alcohol has a chain lower than six carbon atoms.
  • the peptide substance is cyclosporin present in an amount ranging from 0.1 to 50 percent based on the weight of the preparation. More preferably, the peptide substance is cyclosporin A present in an amount ranging from 0.5 to 30 percent based on the weight of the preparation.
  • the formulation of the invention may comprise additional components.
  • the formulation comprises a tenside.
  • the formulation comprises a co-surfactant.
  • the formulation comprises a co-solvent.
  • the formulation may be made available in many forms.
  • the formulation may be suitable for oral administration in the form of a liquid solution or a gelatin capsule.
  • the formulation can also be suitable for topical administration.
  • the formulation can be selected from gels, creams, ointments, and other substances having a semi-solid form.
  • the present invention relates to a pharmaceutical preparation which includes a) a peptide substance; b) at least one component selected from the group consisting of a polyoxyalkyl, a vinyl polymer, an acrylic polymer, linear polymers thereof, and crosslinked polymers thereof; and c) at least one component selected from the group consisting of monoesters of fatty acids containing alcohols having a chain lower than six carbon atoms.
  • the component a) comprises the vinyl polymers such as those sold under the trade name known as Carbomer ® ; the copolymerization products thereof including crosslined copolymers; and C 10 -C 30 cross-linked alk lacrylates. Examples of the following are sold under the commercial name of Pemulen ® . Polyoxyalkyl copolymers are commercially available, for instance under the trade name Pluronic ® .
  • the component b) preferably comprises lipophilic solvents such as isopropyl myristate, isopropyl palmitate, isopropyl stearate or other monoesters of saturated or unsaturated fatty acids having an alkyl alcohol of less than 6 carbon atoms.
  • the component a) is present in percentages ranging from 0,01 to 10% by weight, preferably from OJ to 5%; whereas the component b) is present in percentages from 1 to 50% by weight, preferably from 5 to 25%.
  • other components can also be present to improve the fluidity characteristics of the composition, such as, for example, alcohols, glycols, or to lower the interface tension of the solution particles when these are in contact with body fluids, such as those of the gastro-intestinai tract or of the circulatory system: for this purpose, the presence of tensides and co-surfactants, such as the ionic and non-ionic components of acidic, basic or zwitterionic nature, particularly those selected from the group consisting of lecithins or polyoxyethylated derivatives of tocopherol esters.
  • tensides and co-surfactants such as the ionic and non-ionic components of acidic, basic or zwitterionic nature, particularly those selected from the group consisting of lecithins or polyoxyethylated derivatives of tocopherol esters.
  • Co-surfactants and co-solvents such as alkylene or polyalkylene glycols, alkylene carbonates, triacetin, tributyl glycerol, esters of glycerol with monocarboxylic organic acids with no more than 6 carbon atoms, betaines, alkylbetaines or alkylamidobetaines may be used.
  • Co-solvents which also may be used, include, for example, straight or branched alkyl alcohols up to 4 carbon atoms selected from group consisting of ethanol, n-propanol, n-butanol, isopropanol, tert-butanol or isobutanol can also be used as fluidifiers.
  • Peptide substances which can be advantageously used with the formulations of the invention are preferably cyclosporins.
  • the cyclosporins are preferably used in concentrations ranging from 0J to 50% percent by weight of the formulation. Most preferably, cyclosporin A is used in a concentration ranging from 0.5 to 30% w/w of the formulation.
  • compositions of the present invention can form emulsions with a high number of droplets in a dispersed phase as a result of the addition of water.
  • the resulting emulsions may obtain desirable levels of dispersion degree and stability which can lead to a high adso ⁇ tion profile of the carried peptide substance.
  • the following table shows the adsorption profiles of cyclosporin in rats treated orally with a single dose (5 mg/rat, equivalent to about 15 mg/kg) of different formulations selected from the described examples. The adso ⁇ tion profiles were measured over a 24 hour period.
  • compositions of the present invention can be used for oral, topical administration, and also through the parenteral, transmucosal or nasal route.
  • liquid solutions or suspensions can be administered as such or they can be distributed in gelatin capsules.
  • Suitable administration forms for the topical route are, for example, gels, creams, and ointments and other substances having a semi-solid form.
  • the topical administration can be very useful in the treatment of psoriasis or of other cutaneous forms of autoimmune diseases, when the carried medicament is a cyclosporin and particularly cyclosporin A.
  • Pharmaceutical preparations may optionally contain other components such as, for example, the present invention, thickening agents and carrier structurant agents to keep the peptide substance in an administration site for the time required for adso ⁇ tion while reducing the side effects typically associated with systemic therapy of effective doses of peptide components.
  • Carbomer 1342 refers to various excipients.
  • the excipient refers to those components sold as Pemulen ® , or with the denomination "C 10 -C 30 Alkyl Acrylates Crosspolymers" produced by BF Goodrich.
  • Tocopherol PEG 1000 succinate refers to an excipient known under the commercial name of
  • Caprylic-Capric Triglyceride refers to an excipient known under the commercial name of Miglyol 812, produced by Dynamit Nobel AG, and may include similar products.
  • Carbomer 940 refers to an excipient known under the commercial name Carbopol ® 940 NF produced by BF Goodrich.
  • Example 1 A 10% cyclosporin solution is prepared with the following composition: Cyclosporin 10.00 % w/v
  • Pemulen ® TR2 is solubilized in propylene glycol. Cyclosporin and Vitamin E TPGS are solubilized in the isopropanol/isopropyl myristate mixture. The two solutions are combined with stirring. The final solution can be distributed in soft or hard gelatin capsules.
  • Example 2 A 10% cyclosporin solution is prepared with the following composition: Cyclosporin 10.00 % w/v
  • Pemulen ® TRI is dissolved in propylene glycol. Cyclosporin and vitamin E
  • TPGS are solubilized in the ethanol/isopropyl myristate mixture.
  • the two solutions are combined with stirring.
  • the final solution can be distributed in a dropping bottle.
  • the solution was used in one of the bioavailability tests described above, the results of which are shown in table 1.
  • Example 3 A 10% cyclosporin solution is prepared with the following composition: Cyclosporin 10.00 % w/v Absolute ethanol 10.00 % w/v
  • Triacetin q.s. to 100.00 ml
  • Pemulen ® TR2 is dissolved in triacetin. Cyclosporin is solubilized in the ethanol/isopropyl myristate mixture. The two solutions are combined with stirring.
  • the final solution is distributed in soft gelatin capsules suitable to contain unitary doses of 25 to 100 mg. of cyclosporin.
  • Carbomer 1342 0.02 % w/v Caprylic-Capric Triglyceride q.s. to 100.00 ml
  • Pemulen ® TR2 is dissolved in Miglyol 812. Cyclosporin is solubilized in the ethanol/isopropyl myristate mixture. The two solutions are combined with stirring. The final solution can be distributed in soft gelatin capsules or dosed in bottles of 50 ml unitary content.
  • Example 5 The composition is the same as that of example 4, but the caprylic-capric triglyceride is replaced by a vegetable, mineral or animal oil.
  • Carbomer 1342 0.20 % w/v
  • Carbomer 1342 1.00 % w/v
  • the final solution can be distributed in gelatin capsules. Part of the solution was distributed in bottles fitted with a doser nozzle, for use as a dermatologic lotion.
  • Carbomer 940 1.00 % w/v Triethanolamine q.s. to pH 6-7
  • a gel is obtained which is easy and convenient to use, such as, for example, the topical administration of the peptide substance on body areas affected by psoriasis.
  • the gel is distributed in innerly protected aluminum tubes, with a 50 g unitary content.
  • Example 9 A 10% cyclosporin solution with the following composition is prepared: Cyclosporin 10.00 % w/v Isopropanol 25.00 % w/v
  • Pemulen ® TR2 is dissolved in propylene glycol. Cyclosporin is solubilized in the isopropanol/isopropyl myristate mixture. The two solutions are combined with stirring.

Abstract

L'invention porte sur une préparation pharmaceutique comprenant a), une substance peptidique, b), au moins un constituant sélectionné dans le groupe constitué d'un polyoxyalkyle, d'un polymère vinylique, d'un polymère acrylique, de leurs polymères linéaires et de leurs copolymères réticulés et c), d'au moins un constituant sélectionné dans le groupe constitué de monoesters d'acides gras contenant des alcools ayant une chaîne de moins de six atomes de carbone.
PCT/GB1996/001772 1995-07-25 1996-07-24 Compositions pharmaceutiques contenant de la cyclosporine et d'autres substances peptidiques WO1997004795A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65285/96A AU6528596A (en) 1995-07-25 1996-07-24 Pharmaceutical compositions containing cyclosporin or other peptide substances

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI95A001610 1995-07-25
IT95MI001610A IT1277338B1 (it) 1995-07-25 1995-07-25 Composizioni farmaceutiche di ciclosporina o altre sostanze peptidiche

Publications (2)

Publication Number Publication Date
WO1997004795A2 true WO1997004795A2 (fr) 1997-02-13
WO1997004795A3 WO1997004795A3 (fr) 1997-03-13

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/001772 WO1997004795A2 (fr) 1995-07-25 1996-07-24 Compositions pharmaceutiques contenant de la cyclosporine et d'autres substances peptidiques

Country Status (3)

Country Link
AU (1) AU6528596A (fr)
IT (1) IT1277338B1 (fr)
WO (1) WO1997004795A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0982035A1 (fr) * 1998-08-18 2000-03-01 Panacea Biotec Limited Composition de cyclosporine comprenant un support hydrophile
WO2003015789A2 (fr) * 2001-08-15 2003-02-27 Leo Pharma A/S Composition pharmaceutique pour application cutanee
US7919113B2 (en) 1999-12-30 2011-04-05 Yissum Research Development Company Of The Hebrew University Of Jerusalem Dispersible concentrate lipospheres for delivery of active agents
EP3305312A4 (fr) * 2015-06-05 2019-02-27 Maruho Co., Ltd. Préparation à usage externe pour administration transdermique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003157A1 (fr) * 1992-07-28 1994-02-17 Poli Industria Chimica S.P.A. Compositions pharmaceutiques utiles dans l'apport transmuqueux de peptides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003157A1 (fr) * 1992-07-28 1994-02-17 Poli Industria Chimica S.P.A. Compositions pharmaceutiques utiles dans l'apport transmuqueux de peptides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0982035A1 (fr) * 1998-08-18 2000-03-01 Panacea Biotec Limited Composition de cyclosporine comprenant un support hydrophile
US7919113B2 (en) 1999-12-30 2011-04-05 Yissum Research Development Company Of The Hebrew University Of Jerusalem Dispersible concentrate lipospheres for delivery of active agents
WO2003015789A2 (fr) * 2001-08-15 2003-02-27 Leo Pharma A/S Composition pharmaceutique pour application cutanee
WO2003015789A3 (fr) * 2001-08-15 2004-03-04 Leo Pharma As Composition pharmaceutique pour application cutanee
EP3305312A4 (fr) * 2015-06-05 2019-02-27 Maruho Co., Ltd. Préparation à usage externe pour administration transdermique

Also Published As

Publication number Publication date
AU6528596A (en) 1997-02-26
WO1997004795A3 (fr) 1997-03-13
ITMI951610A0 (it) 1995-07-25
IT1277338B1 (it) 1997-11-10
ITMI951610A1 (it) 1997-01-25

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