WO1993006854A1 - Compositions pharmaceutiques comportant une calcitonine, un glycyrrhizinate en tant que stimulateur d'absorption, et du benzyle - Google Patents

Compositions pharmaceutiques comportant une calcitonine, un glycyrrhizinate en tant que stimulateur d'absorption, et du benzyle Download PDF

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Publication number
WO1993006854A1
WO1993006854A1 PCT/EP1992/002321 EP9202321W WO9306854A1 WO 1993006854 A1 WO1993006854 A1 WO 1993006854A1 EP 9202321 W EP9202321 W EP 9202321W WO 9306854 A1 WO9306854 A1 WO 9306854A1
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WIPO (PCT)
Prior art keywords
glycyrrhizinate
benzyl alcohol
calcitonin
composition
composition according
Prior art date
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PCT/EP1992/002321
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English (en)
Inventor
Laura Chiodini
Teodoro Fonio
Mario Pinza
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Smithkline Beecham Farmaceutici 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.)
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Application filed by Smithkline Beecham Farmaceutici S.P.A. filed Critical Smithkline Beecham Farmaceutici S.P.A.
Priority to BR9206707A priority Critical patent/BR9206707A/pt
Priority to JP5506629A priority patent/JPH07500099A/ja
Priority to EP92920956A priority patent/EP0607229A1/fr
Publication of WO1993006854A1 publication Critical patent/WO1993006854A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to novel pharmaceutical compositions containing calcitonins, and to a novel method of enhancing the absorption of a calcitonin across a mucosal membrane.
  • the calcitonins are a class of pharmacologically active peptides, of both natural and synthetic origin, which contain approximately thirty two amino acids, and which have the ability to regulate serum calcium levels.
  • calcitonins including e.g. natural human, salmon and eel calcitonins and the synthetic eel calcitonin analogue elcatonin are now commercially available and commonly employed, e.g. in the treatment of Paget's disease, Sudeck's disease and osteoporosis.
  • choline esters EP 214898
  • acyl carnitines EP 215697
  • aldoses and glucosamines Japanese Pat. Appl. No. 61 126034
  • ascorbates and salicylates EP 37943
  • alpha-cyclodextrin EP 0094157
  • pyroglutamate esters EP 173990
  • chelating agents US 4,476,116
  • benzyl alcohol and polyethylene glycol 400 EP 371010
  • compositions comprising a calcitonin and a glycyrrhizinate are described in our EPA 327756, which includes both liquid and solid formulations.
  • Liquid formulations conventionally contain a preservative and EPA 327756 refers to the use of alkyl p-hydroxybenzoates (parabens) such as methyl and propy p-hydroxybenzoate as suitable preservatives.
  • the present invention provides pharmaceutical compositions comprising a calcitonin; an effective amount of an absorption enhancer which is a glycyrrhizinate; an effective amount of benzyl alcohol and a pharmaceutically acceptable carrier.
  • the present invention also provides a method of enhancing th absorption of a calcitonin across a mucosal membrane, which method comprises co-administering with the calcitonin an effective amount of an absorption enhancer which is a glycyrrhizinate, and an effective amount of benzyl alcohol.
  • glycyrrhizinate Whilst preservatives are generally only used in liquid formulations, absorption enhancers are required in both liquid and solid formulations of calcitonins, and hence the present invention includes within its scope both solid and liquid compositions.
  • glycyrrhizinate as used herein is intended to mean both glycyrrhizinic acid and its carboxylate salts.
  • Particular glycyrrhizinate salts are ammonium glycyrrhizinat and the alkali metal salts e.g. sodium glycyrrhizinate and potassium glycyrrhizinate.
  • a preferred salt is ammonium glycyrrhizinate.
  • calcitonin as used herein is intended to refer to that class of pharmacologically active polypeptides includin not only naturally occurring calcitonins but also various derivatives and analogues thereof, e.g. in which one or more of the amino acid residues or sequences naturally present is omitted, replaced, reversed or otherwise derivatised or in which the N- or C-terminal is modified.
  • calcitonin as used hereinafter, is intende to mean all such calcitonins whether naturally occurring or synthetic.
  • calcitonins examples include: human calcitonin.
  • Chemical Abstract Service Registry Number (CAS RN) 21215-62-3, which has the structure:
  • calcitonins wherein one or more amino acids have been omitted are the des-[Ser 2 , Tyr- ⁇ 2]—Gly ⁇ -calcitonins described in US 4,597,900 and the des-[Tyr 22 ]-salmon calcitonin described in US 4,304,692.
  • Th preparation and properties of elcatonin and related 1,7- dicarbacalcitonins are described in British Patent Number 1,516,947 (Toyo Jozo) .
  • compositions of the present invention suitably can be administered by methods known in the art for transmucosal an transdermal delivery of pharmacologically active substances.
  • the compositions can be administered to, for example, the nasal, sublingual, buccal, rectal, vaginal and colonic mucos and to the skin. They can take the form of drops, aerosols, tablets, capsules, powders, gels, ointments, inserts, suppositories, pessaries, patches and membranes.
  • the compositions can also take the form of enterically coated solid oral compositions as described in, for example, EP 127535 (Hadassah Medical Organisation) .
  • the compositions for sublingual and buccal administration can also take the form of wafers as described in PCT/GB91/00651. Such wafers are formed substantially from starch, and suitably have a thickness of from 0.3 to 1.0 mm.
  • compositions are those intended for administratio to the nasal, buccal, sublingual, rectal and vaginal mucosa.
  • compositions When the composition is intended for delivery to the nasal mucosa, particular dosage forms are solutions, aerosols, drops, gels and powders.
  • Particular dosage forms for buccal and sublingual administration are gels, suspensions, tablets, patches, powders, ointments, solutions, aerosols and wafers.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in a sealed container.
  • the sealed container can take the form of a cartridge or refill for use with an atomising device, or it can take the form of a unitary dispensing device such as a single dose nasal inhaler (see French Patent Application FR 2578426) or an aerosol dispenser fitted with a metering valve and which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • aerosol dispensers are well known in the art.
  • the aerosol dosage forms can also take the form of a pump-atomiser and such forms are also well known in the art.
  • the atomising or dispensing devices for dispensing aerosol sprays typically are designed to dispense particles of a size greater than 1 micrometres. In order to ensure that significant quantities of the composition remain in contact with the oral or nasal mucosa, and are not inhaled, the particles suitably are approximately 10-160 micrometres in size.
  • the viscosity of the liquid composition can b adjusted as necessary according to known methods to ensure that the composition is sprayable.
  • compositions When the composition is intended for application to the rectal and vaginal mucosa particular dosage forms include pessaries, suppositiories, solutions, foams, suspensions, gels, ointments, tablets and soft gelatin capsules.
  • compositions for rectal or vaginal administration are generally presented as a solid suppository or a semisolid or liquid formulation filled into a soft gelatin capsule. It will be appreciated therefore that the excipients for use in such suppository or capsule formulations will be selected an if necessary admixed to give a formulation of the desired consistency at room and body temperatures.
  • the suppository base or carrier may for example comprise one or more components selected from an oil, a fat, a polyglycolyse glyceride and a polyethylene glycol.
  • the oil and/or fat preferably comprises one or more triglycerides as the main component, such as coconut oil, fractionated coconut oil (e.g.
  • a saturated or unsaturated polyglycolysed glyceride may be for example a saturated polyglycolysed glyceride consisting of C ⁇ -i ⁇ glycerides and polyethylene glycol esters such as are available under the trade name Gelucire e.g.
  • Gelucire 35/10, 37/02 or 44/14 a saturated polyglycolysed CQ-CI Q glyceride such as that available under the trade name Labrasol; or an unsaturated polyglycolysed glyceride consisting of C16-C20 glycerides a polyethylene glycol esters such as those available under th trade name Labrafils e.g. Labrafil WL 2609 BS or M 2125 CS.
  • the polyethylene glycol component is preferably liquid at room temperature such as polyethylene glycol-200, 300, 400 or 600, whereas for a soli suppository a polyethylene glycol of higher molecular weight is preferred.
  • the relative proportions of the excipients will of course depend inter alia on the consistency of the formulation required.
  • compositions containing a polyglycolysed glyceride optionall with a polethylene glycol are preferred. Such compositions can also be adapted for oral administration e.g. in hard or soft gelatin capsules, which are preferably enterically coated.
  • composition When the composition is enterically coated and is intended for oral administration, typically it can take the form of a tablet or capsule coated with a coating agent which ensures passage of the calcitonin through the stomach and its subsequent release preferably in the colon.
  • Suitable coating agents include anionic polymers such as acrylic acid/methacrylic acid ester copolymers (e.g. Eudragit S) .
  • the solvents or liquid carriers used in the present formulations are preferably aqueous but can also be chosen from the physiologically acceptable non-aqueous solvents.
  • non-aqueous solvents or carriers are alcohols, particularly polyhydroxy alcohols such as propylene glycol and glycerol, and vegetable and mineral oils.
  • Such non- aqueous solvents or carriers can be added in various concentrations to water to form solutions, oil-in-water emulsions and water-in-oil emulsions.
  • the solvent preferably is water.
  • the liquid formulations of the present invention can contain excipients such as antioxidants, stabilisers, preservatives, agents for adjusting viscosity (e.g. Carbapol, Keltrol or cellulose derivatives), agents for adjusting tonicity (e.g. sodium chloride, glycine or mannitol) , and buffering agents. If desired a further preservative eg. parabens may be used in addition to benzyl alcohol, but in general this is not necessary.
  • excipients such as antioxidants, stabilisers, preservatives, agents for adjusting viscosity (e.g. Carbapol, Keltrol or cellulose derivatives), agents for adjusting tonicity (e.g. sodium chloride, glycine or mannitol) , and buffering agents. If desired a further preservative eg. parabens may be used in addition to benzyl alcohol, but in general this is not necessary.
  • compositions can also contain a protease inhibitor, preferably a non-surfactant protease inhibitor, for example as described in EP 127535.
  • a protease inhibitor preferably a non-surfactant protease inhibitor, for example as described in EP 127535.
  • compositions can be made according to well known pharmaceutical procedures, see for example Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, 1985.
  • Soft gelatin capsules may be prepared for example as described in WO 84/03417 or EPA 122463.
  • Wafer formulations may be prepared for example as described in PCT/GB91/00651.
  • the active ingredient may be incorporated into the wafer mix prior to forming the wafer, or applied to the wafer in the form of a layer or a spray.
  • compositions of the present invention can be used in the treatment of diseases such as Paget's disease (osteitis deformans) , osteoporosis, including post- enopausal osteoporosis; Sudeck's disease and various hypercalcaemic conditions (see, for example, the Physician's Desk Reference 42nd Edition, 1988, pages 1796 and 1797) .
  • diseases such as Paget's disease (osteitis deformans) , osteoporosis, including post- enopausal osteoporosis; Sudeck's disease and various hypercalcaemic conditions (see, for example, the Physician's Desk Reference 42nd Edition, 1988, pages 1796 and 1797) .
  • compositions will be administered to the patient in dosages which contain an amount of calcitonin effective to treat the disease in question.
  • a unit dose of a composition intended for human use typically contains betwee 1 and 400 International Units (I. ⁇ .) of a calcitonin.
  • a unit dose preferably contains from 5 to 200 I. ⁇ .
  • a typical dosage regimen for elcatonin is from 5 to 200 I. ⁇ . per day which may be administered in a single dose or in divided doses, for example on consecutive or on alternate days.
  • International Unit refers to the appropriate International Reference Preparation (I.R.P.) of human, salmon or porcine calcitonins, or elcatonin, established by the National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, United Kingdom.
  • the volume of a unit dose typically is in the range 50 to 130 mcl.
  • the pH of the compositions of the present invention can vary within a broad range according to the chemicophysical properties of the different ingredients in the compositions.
  • the pH of the composition is in the range from pH 3 to 8, preferably from approximately pH 4 to approximately pH 7.
  • a buffering agent may be included in the composition.
  • buffering agents include citrates, for example a mixture of citric acid and sodiu citrate, acetates and phosphates.
  • an alkali metal hydroxide e.g. sodium hydroxide may be incorporated to regulate the pH.
  • the concentration of the benzyl alcohol is between 0.1 and 5.0% (w/w) of the total weight, of the composition.
  • the benzyl alcohol is suitably present in an amount corresponding to between 0.5 g and 4 g per 100 ml of composition.
  • the benzyl alcohol is present in an amount corresponding to approximately 2 g/100 ml.
  • the benzyl alcohol is suitably present in an amount corresponding to between 0.1 and 1 g per 100 g of composition.
  • the benzyl alcohol is present in an amount corresponding to between 0. g and 0.5 g per 100 g.
  • the concentration of the glycyrrhizinate absorption enhance typically is at least 0.1% (w/w), suitably 0.1 to 10% (w/w), and preferably 0.2 to 5% (w/w) of the total weight of the composition.
  • the glycyrrhizinate suitably is present in an amount corresponding to between 0.5g and 5g per 100 ml of composition.
  • the glycyrrhizinate is present in a amount corresponding to approximately 2g/100 ml.
  • the glycyrrhizinate is suitably present in an amount corresponding to between 0.1 g and 2 g per 100 g of composition.
  • the glycyrrhizinate is present in an amount corresponding to between 0.2 g and 1 g per 100 g.
  • the final pharmaceutical form i.e liquid solution or gel
  • the final pharmaceutical form can also depend upon the pH, the ionic strength of the solution and the concentration of glycyrrhizinate.
  • compositions having a pH of about 5.5 and above will exist as liquids whilst composition having a lower pH value will tend to be more viscous and, at around pH 4.5, will exist in a gel form.
  • Elcatonin (meg) (6500 I.U./mg potency) Ammonium glycyrrhizinate (g) Citric acid (mg) Sodium citrate dihydrate Sodium chloride (mg) Benzyl alcohol (g) Distilled water IN NaOH
  • Examples 1 to 3 were prepared by mixing together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, distilled water and sodium hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and elcatonin were then added.
  • compositions were prepared according to the method described in Examples 1 to 3.
  • compositions were prepared according to the method described in Examples 1 to 3.
  • Elcatonin (meg) (6500 I.U./mg potency) Ammonium glycyrrhizinate (g) Citric acid (mg) Sodium citrate dihydrate (mg)
  • Elcatonin (meg) (6500 I.U./mg potency) Ammonium glycyrrhizinate (g) Citric acid (mg) Sodium citrate dihydrate (mg) Sodium chloride (mg) Benzyl alcohol (g) Methyl p-hydroxybenzoate (mg) Propyl p-hydroxybenzoate (mg) Distilled water IN NaOH
  • Examples 16 to 19 were prepared by mixin together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, distilled water and sodium hydroxide in a water bath regulated at a temperature of abou 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and elcatonin were then added.
  • compositions were prepared according to the method described in Examples 1 to 3
  • Elcatonin (meg) (6500 I.U./mg potency) Ammonium glycyrrhizinate (g) Citric acid (mg) Sodium citrate dihydrate (mg) Sodium chloride (mg) Benzyl alcohol (g) Distilled water q.s. to 100 ml
  • Example 22 The formulation of Example 22 was prepared by mixing togethe the ammonium glycyrrhizinate, acetic acid, sodium acetate trihydrate, sodium chloride, distilled water and sodium hydroxide in a water bath regulated at a temperature of abou 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and elcatonin were then added.
  • the preparations were administered intranasally with a small catheter, in the volume of 100 mcl/kg body weight (corresponding to 2 I.U./kg), to groups of 10 Sprague Dawley rats weighing 160 ⁇ 20 g.
  • TBE tribromoethanol
  • Serum calcium concentration was measured (with an atomic absorption spectrophotometer VARIAN 30/40) on blood samples obtained in each animal, from the caudal vein, 0, 30, 60, 120 and 180 min after administration of the products.
  • the AUC (0-180 min) values were calculated; being AUC calculated on the residual serum calcium, a lower AUC is indicative of a greater pharmacodynamic effect.
  • the AUC (0-180 min) values and the differences ( ⁇ AUC) between the test preparations and reference preparations A and B in comparison with that of the reference preparation C, which does not contain either ammonium glycyrrhizinate or benzyl alcohol, are reported in Table 7.
  • the formulations of Examples 23 and 24 are prepared by mixin together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, distilled water and sodium hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and salmon calcitonin are then added.
  • Eel calcitonin (meg) (5000 I.U./mg potency) Ammonium glycyrrhizinate (g) Citric acid (mg) Sodium citrate dihydrate (mg) Benzyl alcohol (g) Sodium chloride (mg) Distilled water IN NaOH
  • Examples 25 and 26 are prepared by mixin together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, distilled water and sodium hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and eel calcitonin are then added.
  • Examples 27 and 28 are prepared by mixin together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, distilled water and sodium hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and chicken calcitonin II are then added.
  • the formulations of Examples 29 and 30 are prepared by mixin together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, distilled water and sodium hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and human calcitonin are then added.
  • the formulations of Examples 31 and 32 are prepared by mixin together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, distilled water and sodium hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and pig calcitonin are then added.
  • the formulations of Examples 33 and 34 are prepared by wetting the lactose with, benzyl alcohol and with an aqueous solution of elcatonin and drying under vacuum. The dried powder is mixed with ammonium glycyrrhizinate and the final mixture is placed into hard gelatine capsules (25 mg each capsule) .
  • the powder is administered, after having pierced the capsules, using a nasal insufflator.
  • the formulations of Examples 35 and 36 are prepared by mixing together the sucrose, the mannitol and the lactose. The resulting mixture is wetted with benzyl alcohol and with an aqueous solution of elcatonin, granulated through a stainless steel screen and dried under vacuum. The dried granules are mixed with polyethylene glycol and ammonium glycyrrhizinate and then compressed into tablets of 120 mg each.
  • Polyethylene glycol 6000 (g) Carbopol 934 (g) Lactose q.s. to (g)
  • the formulations of Examples 37 and 38 are prepared by mixing together the sucrose, the mannitol and the lactose. The resulting mixture is wetted with benzyl alcohol and with an aqueous solution of elcatonin, granulated through a stainless steel screen and dried under vacuum. The dried granules are mixed with ammonium glycyrrhizinate, Carbopol and polyethylene glycol and then compressed into tablets of 150 mg each.
  • Elcatonin (mg) (6500 I.U./mg potency) Ammonium glycyrrhizinate (g) Benzyl alcohol (g) Pregelatinized starch (g) Magnesium stearate (g) Lactose q.s. to (g) Eudragit S (g) Polyethylene glycol 6000 (g)
  • the formulations of Examples 39 and 40 are prepared by mixin together the pregelatinized starch and the lactose. The resulting mixture is wetted with benzyl alcohol and with an aqueous solution of elcatonin, granulated through a stainles steel screen and dried under vacuum. The dried granules ar mixed with ammonium glycyrrhizinate and magnesium stearate and then compressed into tablets of 210 mg each.
  • the tablets are coated with an aqueous suspension of polyethylene glycol and Eudragit, to a final weight of 232 mg/tablet.
  • Dosage form for vaginal administration is aqueous suspension of polyethylene glycol and Eudragit, to a final weight of 232 mg/tablet.
  • the formulations of Examples 41 and 42 are prepared by mixin together the ammonium glycyrrhizinate, the corn starch, the adipic acid and the lactose. The resulting mixture is wetted with benzyl alcohol and with an aqueous solution of elcatonin, granulated through a stainless steel screen and dried under vacuum. The dried granules are mixed with sodium bicarbonate and magnesium stearate and then compresse into tablets of 1.6 g each.
  • Example 43 The formulation of Example 43 is prepared by mixing together the ammonium glycyrrihizinate, benzyl alcohol and distilled water in a water bath regulated at a temperature of about 70°C. The solution is cooled to about 40°C, elcatonin is dissolved and then the resulting solution is incorporated into hard fat melted at about 40°C.
  • the final mixture is poured into suppository moulds and cooled to room temperature, thus obtaining suppositories of 1.5 g each.
  • Elcatonin (6500 I.U./mg potency) Polyethylene glycol 600 (g) Gelucire 44/14 (g) Distilled water (g) Ammonium glycyrrhizinate (g) Benzyl alcohol (g) Sodium chloride (mg) Sodium citrate dihydrate (mg) Sodium hydroxide (mg) Citric acid (mg)
  • Examples 44 to 46 were prepared by mixin together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, sodium hydroxide, distilled water and elcatonin in a water bath regulated at a temperature of about 70°C.
  • Elcatonin (6500 I.U./mg potency) Polyethylene glycol 600 (g) Witepsol S55 (g) Miglyol 812 (g) Distilled water (g) Ammonium glycyrrhizinate (g) Benzyl alcohol (g) Sodium chloride (mg) Sodium citrate dihydrate (mg) Sodium hydroxide (mg) Citric acid (mg)
  • Examples 47 to 49 were prepared by mixing together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, sodium hydroxide, distilled water and elcatonin in a water bath regulated at a temperature of about 70°C.
  • Example 50 The formulation of Example 50 is prepared by mixing together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, sodium chloride, Carbopol 934, sodium hydroxide and part of distilled water in a water bath regulated at a temperature of about 70°C. To the resulting gel, cooled to room temperature, a solution of elcatonin and benzyl alcohol in the remaining part of distilled water, is then added.
  • the final gel is filled into patches of 500 mg each.
  • Formulations for nasal, sublingual, buccal, rectal or vaginal administration are provided.
  • Examples 51 and 52 were prepared by mixing together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, mannitol, distilled water and sodium hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and elcatonin were then added.
  • Examples 53 and 54 were prepared by mixing together the ammonium glycyrrhizinate, citric acid, sodium citrate dihydrate, glycine, distilled water and sodiu hydroxide in a water bath regulated at a temperature of about 70°C. To the resulting solution cooled to room temperature, benzyl alcohol and elcatonin were then added.
  • compositions are prepared in an analogous manner to Example 1.

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Abstract

Compositions pharmaceutiques comportant une calcitonine, une quantité efficace de glycyrrhizinate en tant que stimulateur d'absorption, une quantité efficace d'alcool benzylique, ainsi qu'un excipient pharmaceutiquement acceptable. Elles sont utilisées dans le traitement de pathologies telles que l'ostéoporose.
PCT/EP1992/002321 1991-10-11 1992-10-08 Compositions pharmaceutiques comportant une calcitonine, un glycyrrhizinate en tant que stimulateur d'absorption, et du benzyle WO1993006854A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
BR9206707A BR9206707A (pt) 1991-10-11 1992-10-08 Compostos farmacêuticos contendo uma calcitonina
JP5506629A JPH07500099A (ja) 1991-10-11 1992-10-08 カルシトニン、吸収エンハンサーとしてのグリシルリジン酸塩およびベンジルからなる医薬組成物
EP92920956A EP0607229A1 (fr) 1991-10-11 1992-10-08 Compositions pharmaceutiques comportant une calcitonine, un glycyrrhizinate en tant que stimulateur d'absorption, et du benzyle

Applications Claiming Priority (2)

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ITMI912703A IT1251685B (it) 1991-10-11 1991-10-11 Composizioni farmaceutiche contenenti una calcitonina
ITMI91A002703 1991-10-11

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JP (1) JPH07500099A (fr)
AU (1) AU2683492A (fr)
BR (1) BR9206707A (fr)
CA (1) CA2120755A1 (fr)
IT (1) IT1251685B (fr)
MX (1) MX9205852A (fr)
PT (1) PT100946A (fr)
WO (1) WO1993006854A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2285921A (en) * 1994-01-31 1995-08-02 Leilani Lea Sublingual administration of medicaments
EP0726075A1 (fr) * 1995-02-08 1996-08-14 Therapicon Srl Solutions pharmaceutiques salines non-inorganiques pour administration endonasale
WO1997021448A1 (fr) * 1995-12-13 1997-06-19 Dullatur Limited Preparation de calcitonine
ES2151838A1 (es) * 1997-09-05 2001-01-01 Alfa Wassermann Spa Composiciones farmaceuticas que contienen calcitonina en un dosificador de pulverizado para administracion intranasal.
WO2002028436A1 (fr) * 2000-10-06 2002-04-11 Axcess Limited Activateurs d'absorption
US6699841B2 (en) * 2001-01-30 2004-03-02 Leandro Baiocchi Method of preparing physiologically acceptable aqueous solutions, and solutions thus obtained
WO2004091584A1 (fr) * 2003-04-15 2004-10-28 Axcess Limited Activateurs d'absorption tels que le bht, le bha ou le gallate de propyle
US8314058B2 (en) 2003-04-15 2012-11-20 Axcess Limited Uptake of macromolecules

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EP0156565A2 (fr) * 1984-03-07 1985-10-02 Yamanouchi Pharmaceutical Co. Ltd. Compositions et pansements antipruritiques
EP0327756A2 (fr) * 1987-11-13 1989-08-16 Smithkline Beecham Farmaceutici S.p.A. Compositions pharmaceutiques contenant une calcitonine et un glycyrrhizinate comme promoteur d'absoption
EP0371010A1 (fr) * 1984-11-26 1990-05-30 Yamanouchi Pharmaceutical Co. Ltd. Médicament absorbable à base de calcitonine
EP0471618A1 (fr) * 1990-08-16 1992-02-19 Asahi Kasei Kogyo Kabushiki Kaisha Emulsion contenant de la calcitonine pour l'administration nasale

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EP0156565A2 (fr) * 1984-03-07 1985-10-02 Yamanouchi Pharmaceutical Co. Ltd. Compositions et pansements antipruritiques
EP0371010A1 (fr) * 1984-11-26 1990-05-30 Yamanouchi Pharmaceutical Co. Ltd. Médicament absorbable à base de calcitonine
EP0327756A2 (fr) * 1987-11-13 1989-08-16 Smithkline Beecham Farmaceutici S.p.A. Compositions pharmaceutiques contenant une calcitonine et un glycyrrhizinate comme promoteur d'absoption
EP0471618A1 (fr) * 1990-08-16 1992-02-19 Asahi Kasei Kogyo Kabushiki Kaisha Emulsion contenant de la calcitonine pour l'administration nasale

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2285921A (en) * 1994-01-31 1995-08-02 Leilani Lea Sublingual administration of medicaments
EP0726075A1 (fr) * 1995-02-08 1996-08-14 Therapicon Srl Solutions pharmaceutiques salines non-inorganiques pour administration endonasale
WO1996024370A1 (fr) * 1995-02-08 1996-08-15 Therapicon S.R.L. Solutions pharmaceutiques salines non organiques a administration endonasale d'une calcitonine
US6087338A (en) * 1995-02-08 2000-07-11 Therapicon S.R.L. Pharmaceutical non inorganic saline solutions for endonasal administration of a calcitonin
US6107277A (en) * 1995-02-08 2000-08-22 Therapicon S.R.L. Calcitonin salmon analogues
WO1997021448A1 (fr) * 1995-12-13 1997-06-19 Dullatur Limited Preparation de calcitonine
ES2151838A1 (es) * 1997-09-05 2001-01-01 Alfa Wassermann Spa Composiciones farmaceuticas que contienen calcitonina en un dosificador de pulverizado para administracion intranasal.
GB2368792A (en) * 2000-10-06 2002-05-15 Roger Randal Charles New Absorption enhancers
WO2002028436A1 (fr) * 2000-10-06 2002-04-11 Axcess Limited Activateurs d'absorption
US7303762B2 (en) 2000-10-06 2007-12-04 Axcess Limited Absorption enhancers
US6699841B2 (en) * 2001-01-30 2004-03-02 Leandro Baiocchi Method of preparing physiologically acceptable aqueous solutions, and solutions thus obtained
WO2004091584A1 (fr) * 2003-04-15 2004-10-28 Axcess Limited Activateurs d'absorption tels que le bht, le bha ou le gallate de propyle
EP1620073A1 (fr) * 2003-04-15 2006-02-01 Axcess Limited Activateurs d'absorption tels que le bht, le bha ou le gallate de propyle
US7651995B2 (en) 2003-04-15 2010-01-26 Axcess Limited Absorption enhancers such as e.g. BHT, BHA or propyl gallate
AU2004229216B2 (en) * 2003-04-15 2010-04-01 Axcess Limited Absorption enhancers such as e.g. BHT, BHA or propyl gallate
US8314058B2 (en) 2003-04-15 2012-11-20 Axcess Limited Uptake of macromolecules

Also Published As

Publication number Publication date
PT100946A (pt) 1993-10-29
ITMI912703A0 (it) 1991-10-11
EP0607229A1 (fr) 1994-07-27
AU2683492A (en) 1993-05-03
ITMI912703A1 (it) 1993-04-11
MX9205852A (es) 1993-06-01
IT1251685B (it) 1995-05-19
CA2120755A1 (fr) 1993-04-15
JPH07500099A (ja) 1995-01-05
BR9206707A (pt) 1995-10-31

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