CA2212520A1 - Pharmaceutical non inorganic saline solutions for endonasal administration of a calcitonin - Google Patents
Pharmaceutical non inorganic saline solutions for endonasal administration of a calcitoninInfo
- Publication number
- CA2212520A1 CA2212520A1 CA002212520A CA2212520A CA2212520A1 CA 2212520 A1 CA2212520 A1 CA 2212520A1 CA 002212520 A CA002212520 A CA 002212520A CA 2212520 A CA2212520 A CA 2212520A CA 2212520 A1 CA2212520 A1 CA 2212520A1
- Authority
- CA
- Canada
- Prior art keywords
- calcitonin
- solutions according
- pharmaceutical solutions
- glucamine
- methyl
- 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.)
- Abandoned
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/585—Calcitonins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
-
- 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
Abstract
The subject-matter of the invention are pharmaceutical non inorganic saline solutions for endonasal administration containing: (a) a calcitonin, preferably salmon or alternatively carbacalcitonin (elcatonin), or its pharmaceutically acceptable salts; characterized in that it further contains the organic excipients; (b) N-(methyl)-glucamine or glucamine; (c) tromethamine; (d) citric acid; and (e) polyvinylpyrrolidone ranging from K15 to K120. These are odourless and tasteless and thus have improved patient's compliance not having the undesirable secondary effects of known compositions as well as permit a complete and accurate analysis of the activeprinciple and develop less degradation products during storage.
Description
CA 022l2~20 l997-08-07 WO 96/24370 PcT/~ GJ~ ~ 14 ~
Pharmaceutlcal non ~norganlc sallne solutlons for endonasal admlnlstratlon of a calcltonln.
The invention is concerned with novel pharmaceutical non saline solutions for endonasal administration containing a natural or modified calcitonin, more preferably salmon calcitonin or carbacalcitonin (elcatonin), having enhanced organoleptic characters and a better patient's compliance.
Calcitonins are well-known long chain polypeptides used for convenient prophylaxis and therapy of some diseases, like Paget's disease, hypercalcemia and osteoporosis.
Calcitonin salmon is widely and efficiently adopted for the treatment of the above indications, so that specific monographs have been included in the most qualified pharmacopoeias like Eur. Ph. II Ed., DAB 10 (lg91), BP
88, F.U. IX Ed..
The above pharmacopoeias indicate that calcitonin salmon (dry active ingredient), as acetate salt, shall contain minimum 4,000 I.U. per milligram (biological assay) and not more than 10 % by weight of water and not more than 15 % by weight of acetic acid. Storage condition at about 4~C/8~C is also prescribed for the powder stability.
Already there have been described saline compositions of calcitonin salmon for endonasal administration, which are stabilized with an appreciable quantity of acetic acid, but the presence of acetic acid results in the entire composition having a very unpleasant odour of acetic acid.
CA 022l2~20 l997-08-07 W096/24370 P~~ G~00 Additionally in these compositions it is not possible to analytically establish the exact aliquot of acetic acid included in the active ingredient calcitonin (maximum 15 ~ by weight) and the part of acetic acid, which has been 5 added to the formulations as stabilizing excipient.
In other previous compositions (DE-A 33 35 086), hydrochloric acid has been used to adjust the pH value of the solution. This practice is also very inconvenient because of hydrochloric acid is able to remove acetic acid from the calcitonin acetate salt, thus producing an undesired liberation and odour of acetic acid.
Other publications teach that aliquots of calcitonins, for endonasal administration, therapeutically bioequivalent to those administered by parenteral route, are normally absorbed through the nasal mucosa and are also generally well tolerated. Calcitonins, specifically calcitonin salmon, as acetate salt, is remarkably unstable and, when it is not suitably formulated (bacterial contamination, unsuitable pH values, packed in non nitrogen atmosphere) or stored at temperatures above 8OC, it may develop some degradation products, which have already been described by some authors in the published literature.
In fact in some compositions (DE-A 33 35 086), benzalkonium chloride is used to avoid the bacterial contamination during the storage period and/or utilization, but several studies have indicated that this preserving agent produces some undesirable secondary effects (Am. J. Ophatalmol. 105 (6) [1988]
pages 670 to 673; Contact Dermatitis 17 (1) [1987] pages 41 to 42; Cutis 39 (5) [1987] pages 381 to 383).
CA 02212~20 1997-08-07 W096l24370 PCT~r9G/00~
Thus the problem underlying the present invention is to create novel pharmaceutical solutions for endonasal administration containing a natural or modified calcitonin, preferably salmon or alternatively carbacalcitonin (elcatonin), or its pharmaceutically acceptable salts, which are odourless and tasteless and thus have improved patient's compliance and which does not have the undesirable secondary effects of known compositions but which permits a complete and accurate analysis of the active principle and develops less degradation products during storage.
Surprisingly this has been attained by the present invention.
The invention is based on the surprising recognition that non inorganic saline aqueous solutions containing natural or modified calcitonin as acetate salt (active principle) and ~esides water only organic excipients, described in the most common pharmacopoeias, like pharmaceutically acceptable acids, bases, suspending agents and, optionally c1-4 alkylesters of p-hydroxybenzoic acid fulfil the above requirements.
Surprisingly it has been found that such a composition as defined below is very suitable for endonasal administration, when applied to the nasal mucosa and it is odourless and tasteless, properties that improve the patient's compliance. Moreover the inventive composition allows performance of a complete and accurate analysis of the active ingredient calcitonin salmon (including its volatile impurities, like acetic acid) and minimizes the development of degradation products during the ageing period.
CA 022l2~20 l997-08-07 W096/24370 PCT/~l,'00~1 The present invention provides pharmaceutical non inorganic saline solutions for endonasal administration containing:
S a) a natural or modified calcitonin, preferably salmon or alternatively carbacalcitonin (elcatonin), as its pharmaceutically acceptable salts, characterized in that it further contains the organic excipients described in the most common pharmacopoeias b) N-tmethyl)-glucamine tmeglumine] or alternatively glucamine, c) tromethamine, d) citric acid e) polyvinylpyrrolidone ranging from Kl5 to Kl20.
The active principle and the said organic excipients are dissolved in water.
Advantageously the calcitonin is human calcitonin, eel calcitonin, carbacalcitonin (elcatonin), chicken calcitonin or porcine calcitonin.
Preferred solutions according to the invention contain a) the calcitonin or its pharmaceutically acceptable salts in concentration of 250 I.U./ml to 5,000 I.U./ml, b) the N-(methyl)-glucamine or glucamine in concentrations of 2.0 to 5.0 mg/ml, c) the tromethamine in concentrations of l.0 to 4.0 mg/ml, CA 02212~20 1997-08-07 W096/24370 PCT~96~C~16 d) the citric acid in concentrations of 5.0 to 9.0 mgtml and e) the polyvinylpyrrolidone ranging from K15 to K120 in concentrations of 5 to 25 mg/ml.
It is particularly preferred that the concentration of the calcitonin or its pharmaceutically acceptable salts [a)] is from 400 I.U. to 1,200 I.U./ml.
Furthermore it is particularly preferred that the concentration of the N-(methyl)-glucamine or alternatively glucamine [b)~ is from 2.5 to 4.0 mg/ml.
Moreover it is particularly preferred that the concentration of the tromethamine tc)] is 1.5 to 4.0 mg/ml.
It is also particularly preferred that the concentration of the citric acid [d)] is from 6.0 to 8.0 mg/ml.
Furthermore it is particularly preferred that the concentration of the polyvinylpyrrolidone ranging from K15 to K120 is from 8 to 15 mg/ml.
Moreover it is preferred the solutions according to the invention are sterile formulations.
According to an advantageous embodiment of the invention the solutions according to the invention contain 1 or more C~4 alkylester(s) of p-hydroxybenzoic acid tf)] for additional protection.
Preferably the C14 alkylester(s) of p-hydroxybenzoic acid tf)] is/are methyl p-hydroxybenzoate and/or propyl p-hydroxybenzoate.
CA 02212~20 1997-08-07 W096/24370 PCT/~,5'C~6 It is also preferred that the solutions according to the invention have pH values preferably of from 4.6 to 6Ø
A special particularly preferred solution according to the invention contains:
lx103.U./ml of calcitonin salmon as acetate salt [a)]
3.33 mg/ml of N-(methyl)-glucamine or glucamine [b)]
Pharmaceutlcal non ~norganlc sallne solutlons for endonasal admlnlstratlon of a calcltonln.
The invention is concerned with novel pharmaceutical non saline solutions for endonasal administration containing a natural or modified calcitonin, more preferably salmon calcitonin or carbacalcitonin (elcatonin), having enhanced organoleptic characters and a better patient's compliance.
Calcitonins are well-known long chain polypeptides used for convenient prophylaxis and therapy of some diseases, like Paget's disease, hypercalcemia and osteoporosis.
Calcitonin salmon is widely and efficiently adopted for the treatment of the above indications, so that specific monographs have been included in the most qualified pharmacopoeias like Eur. Ph. II Ed., DAB 10 (lg91), BP
88, F.U. IX Ed..
The above pharmacopoeias indicate that calcitonin salmon (dry active ingredient), as acetate salt, shall contain minimum 4,000 I.U. per milligram (biological assay) and not more than 10 % by weight of water and not more than 15 % by weight of acetic acid. Storage condition at about 4~C/8~C is also prescribed for the powder stability.
Already there have been described saline compositions of calcitonin salmon for endonasal administration, which are stabilized with an appreciable quantity of acetic acid, but the presence of acetic acid results in the entire composition having a very unpleasant odour of acetic acid.
CA 022l2~20 l997-08-07 W096/24370 P~~ G~00 Additionally in these compositions it is not possible to analytically establish the exact aliquot of acetic acid included in the active ingredient calcitonin (maximum 15 ~ by weight) and the part of acetic acid, which has been 5 added to the formulations as stabilizing excipient.
In other previous compositions (DE-A 33 35 086), hydrochloric acid has been used to adjust the pH value of the solution. This practice is also very inconvenient because of hydrochloric acid is able to remove acetic acid from the calcitonin acetate salt, thus producing an undesired liberation and odour of acetic acid.
Other publications teach that aliquots of calcitonins, for endonasal administration, therapeutically bioequivalent to those administered by parenteral route, are normally absorbed through the nasal mucosa and are also generally well tolerated. Calcitonins, specifically calcitonin salmon, as acetate salt, is remarkably unstable and, when it is not suitably formulated (bacterial contamination, unsuitable pH values, packed in non nitrogen atmosphere) or stored at temperatures above 8OC, it may develop some degradation products, which have already been described by some authors in the published literature.
In fact in some compositions (DE-A 33 35 086), benzalkonium chloride is used to avoid the bacterial contamination during the storage period and/or utilization, but several studies have indicated that this preserving agent produces some undesirable secondary effects (Am. J. Ophatalmol. 105 (6) [1988]
pages 670 to 673; Contact Dermatitis 17 (1) [1987] pages 41 to 42; Cutis 39 (5) [1987] pages 381 to 383).
CA 02212~20 1997-08-07 W096l24370 PCT~r9G/00~
Thus the problem underlying the present invention is to create novel pharmaceutical solutions for endonasal administration containing a natural or modified calcitonin, preferably salmon or alternatively carbacalcitonin (elcatonin), or its pharmaceutically acceptable salts, which are odourless and tasteless and thus have improved patient's compliance and which does not have the undesirable secondary effects of known compositions but which permits a complete and accurate analysis of the active principle and develops less degradation products during storage.
Surprisingly this has been attained by the present invention.
The invention is based on the surprising recognition that non inorganic saline aqueous solutions containing natural or modified calcitonin as acetate salt (active principle) and ~esides water only organic excipients, described in the most common pharmacopoeias, like pharmaceutically acceptable acids, bases, suspending agents and, optionally c1-4 alkylesters of p-hydroxybenzoic acid fulfil the above requirements.
Surprisingly it has been found that such a composition as defined below is very suitable for endonasal administration, when applied to the nasal mucosa and it is odourless and tasteless, properties that improve the patient's compliance. Moreover the inventive composition allows performance of a complete and accurate analysis of the active ingredient calcitonin salmon (including its volatile impurities, like acetic acid) and minimizes the development of degradation products during the ageing period.
CA 022l2~20 l997-08-07 W096/24370 PCT/~l,'00~1 The present invention provides pharmaceutical non inorganic saline solutions for endonasal administration containing:
S a) a natural or modified calcitonin, preferably salmon or alternatively carbacalcitonin (elcatonin), as its pharmaceutically acceptable salts, characterized in that it further contains the organic excipients described in the most common pharmacopoeias b) N-tmethyl)-glucamine tmeglumine] or alternatively glucamine, c) tromethamine, d) citric acid e) polyvinylpyrrolidone ranging from Kl5 to Kl20.
The active principle and the said organic excipients are dissolved in water.
Advantageously the calcitonin is human calcitonin, eel calcitonin, carbacalcitonin (elcatonin), chicken calcitonin or porcine calcitonin.
Preferred solutions according to the invention contain a) the calcitonin or its pharmaceutically acceptable salts in concentration of 250 I.U./ml to 5,000 I.U./ml, b) the N-(methyl)-glucamine or glucamine in concentrations of 2.0 to 5.0 mg/ml, c) the tromethamine in concentrations of l.0 to 4.0 mg/ml, CA 02212~20 1997-08-07 W096/24370 PCT~96~C~16 d) the citric acid in concentrations of 5.0 to 9.0 mgtml and e) the polyvinylpyrrolidone ranging from K15 to K120 in concentrations of 5 to 25 mg/ml.
It is particularly preferred that the concentration of the calcitonin or its pharmaceutically acceptable salts [a)] is from 400 I.U. to 1,200 I.U./ml.
Furthermore it is particularly preferred that the concentration of the N-(methyl)-glucamine or alternatively glucamine [b)~ is from 2.5 to 4.0 mg/ml.
Moreover it is particularly preferred that the concentration of the tromethamine tc)] is 1.5 to 4.0 mg/ml.
It is also particularly preferred that the concentration of the citric acid [d)] is from 6.0 to 8.0 mg/ml.
Furthermore it is particularly preferred that the concentration of the polyvinylpyrrolidone ranging from K15 to K120 is from 8 to 15 mg/ml.
Moreover it is preferred the solutions according to the invention are sterile formulations.
According to an advantageous embodiment of the invention the solutions according to the invention contain 1 or more C~4 alkylester(s) of p-hydroxybenzoic acid tf)] for additional protection.
Preferably the C14 alkylester(s) of p-hydroxybenzoic acid tf)] is/are methyl p-hydroxybenzoate and/or propyl p-hydroxybenzoate.
CA 02212~20 1997-08-07 W096/24370 PCT/~,5'C~6 It is also preferred that the solutions according to the invention have pH values preferably of from 4.6 to 6Ø
A special particularly preferred solution according to the invention contains:
lx103.U./ml of calcitonin salmon as acetate salt [a)]
3.33 mg/ml of N-(methyl)-glucamine or glucamine [b)]
2.10 mg/ml of tromethamine [c)]
6.82 mg/ml of citric acid td)]
lO.OO mg/ml of polyvinylpyrrolidone [e)]
l.OO mg/ml of methyl p-hydroxybenzoate [f)]
O.lO mg/ml of propyl p-hydroxybenzoate tf)]
976.65 mg/ml of water for injectable preparations.
A further special particularly preferred solution according to the invention contains:
2x103 I.U./ml of calcitonin salmon as acetate salt [a)]
6.82 mg/ml of citric acid td)]
lO.OO mg/ml of polyvinylpyrrolidone [e)]
l.OO mg/ml of methyl p-hydroxybenzoate [f)]
O.lO mg/ml of propyl p-hydroxybenzoate tf)]
976.65 mg/ml of water for injectable preparations.
A further special particularly preferred solution according to the invention contains:
2x103 I.U./ml of calcitonin salmon as acetate salt [a)]
3.33 mg/ml of N-(methyl)-glucamine or glucamine [b)]
2.10 mg/ml of tromethamine [c)]
6.82 mg/ml of citric acid td)]
CA 02212~20 1997-08-07 10.00 mg/ml of polyvinylpyrrolidone [e)]
1.00 mg/ml of methyl p-hydroxybenzoate tf)]
L
0.10 mg/ml of propyl p-hydroxybenzoate tf)]
976 . 65 mg/ml of water for injectable preparations.
The solutions according to the invention produce minimal degradation products, during the storage period. During an ageing period of 18 months they produce, a very reduced quantity of the inactive degradation product hydroxy-calcitonin. Advantageously the inventive solutions present, after 18 months of shelf-life, a 15 total quantity of degradation product substantially less than 5 ~ by weight limit indicated by various pharmacopoeias [Eur. Ph. II Ed., DAB 10 (1991), BP 88, FU IX Ed.] for calcitonin salmon substance. They are very suitable for endonasal administration, when dispensed in convenient well-known delivery system.
Another more particularly preferred embodiment according to the invention contains:
400 I.U./ml of elcatonin [a)]
3.33 mg/ml of N-(methyl)-~lucamine or glucamine [b)]
2.10 mg/ml of tromethamine lc)]
,.
6.82 mg/ml of citric acid ld)]
lo.00 mg/ml of polyvinylpyrrolidone te)]
1.00 mg/ml of methyl p-hydroxybenzoate [f)]
CA 022l2S20 l997-08-07 W096l24370 P~~ Oq~6 O.lO mg/ml of propyl p-hydroxybenzoate [f)]
976.65mg/ml of water for injectable preparations The surprising advantages of the pharmaceutical solutions according to the invention are summarized as follows:
A) The presence of citric acid [d)], which is useful to adjust the pH values to preferably from 4.6 to 6.0, allows the exact quantity of acetic acid, contained as volatile impurity in calcitonin salmon or in carbacalcitonin (elcatonin) to be determined specifically and precisely, by using conventional analytical methods described in several publications.
In fact, if acetic acid was added to the solution instead of citric acid, it would not be possible to determine, in the formulated preparation, the quantity of the volatile impurity acetic acid (maximum lS% by weight) contained in calcitonin salmon or in carbacalcitonin (elcatonin).
B) The solution according to the invention with citric acid [d)] is organoleptically more acceptable to patients who don't tolerate the unpleasant odour of acetic acid contained in some prior art compositions on the market.
C) Citric acid td)~ has been partially buffered, in the solutions according to the invention, preferably to pH 4.6 to 6.0, by using suitable concentrations of tromethamine [c)] and N-(methyl)glucamine or glucamine [b)] instead of sodium acetate, which can also develop a remarkable odour of acetic acid.
CA 02212~20 1997-08-07 D) Polyvinylpyrrolidone ranging from K15 to K120, te)]
is purposely included into the composition for endonasal administration, since surprisingly it is suitable to prolong the time of contact between the solution and the nasal mucosa for its binding properties.
E) In the solutions of the invention, the presence of preserving agents is optional, because the manufacturing process is carried out to obtain sterile formulations.
Moreover the'nasal bottles equipped with suitable pumps, characterized by absence of air introduction after actuation (dispensing the solution), eliminating, in this way the possible bacteria contamination, during usage. Therefore C1 4 alkylesters of p-hydroxybenzoic acid, particularly methyl p-hydroxybenzoate and/or propyl p-hydroxybenzoate, [f)] are introduced into the solutions of the invention only for additional protection, in case of an exceptional presence of bacteria.
F) More specifically for calcitonin salmon various pharmacopoeias fix an individual limit of 5 % by weight for each related substance {DAB (1991) "Verwandte Substanzen"; Eur. Ph. II Ed. "Substances apparentees";
BP 88 "Related substances"} for calcitonin salmon powder, as acetate salt, while other publications, more specifically Pharmaceutical Research Vol. 9, N. 11, 1992 ("Degradation of Synthetic Salmon Calcitonin Aqueous Solution" - Kang Choon Lee, Yoon Joong Lee, Hyun Myo Song, Chang Ju Chun and Patrick P. DeLuca) indicate that the degradation product is only the reduced calcitonin salmon (dihydro-calcitonin), when the solution presents an acidic pH. Now surprisingly it has been found that the solutions of the invention produce only minimal degradation product during the ageing period of storage.
CA 022l2~20 l997-08-07 W0 96/24370 ~ ;l ,C'~01 1C
The described embodiments of the invention may apply also to other natural or modified calcitonin, alike human calcitonin, eel calcitonin, carbacalcitonin (elcatonin), chicken calcitonin, porcine calcitonin.
The solutions according to the invention can be administered as drops, inhaler or spray, dispensed in suitable well known delivery systems.
The invention is further illustrated by the following examples.
Example l 15 Preparation of 38,461 bottles (1.0 ml) of calcitonin salmon nasal spray 100 I.U./actuation Each actuation dispensing 100 ~l of solution (100 I.U.
of active principle). 1 ml of the solution containing the following constituents:
Ingredient Amount Calcitonin salmon as acetate salt lx103 I.U.
Glucamine 3.33 mg Tromethamine 2.10 mg Citric acid (pH 4.6 to 6.0) 6.82 mg Polyvinylpyrrolidone 10.00 mg Methyl p-hydroxybenzoate 1.00 mg Propyl p-hydroxybenzoate 0.10 mg CA 02212~20 1997-08-07 W096/24370 PCT~6/00446 Water for injectable preparations 976.65 mg The manufacturing process is carried out with the - following conventional steps:
~) 34.0 kg of water for injectable preparations are introduced in a stainless steel dissolutor.
~) In about 3 litres of water is separately prepared a solution containing:
80.77 g of tromethamine +
128.1 g of glucamine +
250.1 g of citric acid y) Once the above solution has been completely dissolved, it is added to the water in the dissolutor.
~) Under constant and slow stirring, 384.61 g of polyvinylpyrrolidone, 38.461 g of methyl p-hydroxybenzoate and 3.846 g of propyl p-hydroxybenzoate and, finally, the remaining quantity of citric acid (12.2 g) are added to yield the pH value of 4.6 to 6.0, which is adjusted, if necessary, by adding 0.1 N NaOH.
~) Separately 38.461 x 106 I.U. of calcitonin salmon as acetate salt are dissolved in about 50 ml of solution, resulting from step y) thus obtaining the mother solution.
Z) Under constant and slow stirring, the mother - - solution of calcitonin salmon and the remaining quantity of water are added to the dissolutor to yield 38.461 kg.
CA 02212~20 1997-08-07 W096/24370 PCTi~~ 116 All manufacturing steps from ~) to ~) are carried out under nitrogen atmosphere at positive pressure.
The obtained solution is filtered for sterilization and subsequently bottled under nitrogen atmosphere at positive pressure according to the well-known methods in the Art.
Example 2 Preparation of 25,000 bottles (2.0 ml) of calcitonin salmon nasal spray 200 I.U:/actuation Each actuation dispensing lO0 ~l of solution (200 I.U.
of active principle). l ml of the solution containing the following constituents:
Ingredient Amount Calcitonin salmon as acetate salt 2x103 I.U.
N-(Methyl)-glucamine 3.33 mg Tromethamine 2.lO mg Citric acid (pH 4.6 to 6.0)6.82 mg Polyvinylpyrrolidone lO.00 mg Methyl p-hydroxybenzoatel.00 mg Propyl p-hydroxybenzoateO.lO mg Water for injectable preparations 976.65 mg CA 022l2~20 l997-08-07 W096/24370 PCT~G/C~~
The manufacturing process is carried out with the following conventional steps:
~) 45.0 kg of water for injectable preparations are introduced in a stainless steel dissolutor.
~) In about 3 litres of water a solution is separately prepared containing:
105.0 g of trometamine +
166.5 g of N-(methyl)-glucamine +
228.5 g of citric acid y) After the complete dissolution of the above solution it is added to the water in the dissolutor.
~) Under constant and slow stirring, 500.0 g of polyvinylpyrrolidone, 50.0 g of methyl p-hydroxybenzoate and 5.0 g of propyl p-hydroxybenzoate and, finally, the remaining quantity of citric acid (12.5 g) are added to yield the pH value of 4.6 to 6.0, which is adjusted, if necessary, by adding O.1 N NaOH.
~) Separately a mother solution of calcitonin salmon as acetate salt is prepared by dissolving l x 107 I.U. of this active principle in about 50 ml of solution resulting from step y).
~) Under constant and slow stirring, the mother solution of calcitonin salmon and the remaining quantity of water are added to the dissolutor to yield 50 kg.
CA 022l2~20 l997-08-07 W096/24370 PCT/~GIC~1~C
All manufacturing steps from ~) to ~) are carried out under nitrogen atmosphere at positive pressure.
The obtained solution is sterilized and bottled under nitrogen atmosphere at positive pressure according to the well-known methods in the Art.
Example 3 Preparation of lO,OOO bottles (l.6 ml) of carbacalcitonin (elcatonin) nasal spray 40 I.U./actuation.
Each actuation dispensing lOO ~l of solution (40 .U. of lS active principle).
l ml of the solution containing the following constituents:
Ingredient Amount Elcatonin 400 I.U.
N-(Methyl)-glucamine 3.33 mg Tromethamine 2.lO mg Citric acid (pH 4.6 to 6.0)6.82 mg Polyvinylpyrrolidone lO.OO mg Methyl p-hydroxybenzoatel.OO mg Propyl p-hydroxybenzoateO.lO mg Water for injectable preparations 976.65 mg - - -CA 02212~20 l997-08-07 W096/24370 PCT/~l~C/~516 The manufacturing process is carried out with the following conventional steps :
- ~) 13.5 Kg of water for injectable preparations are introduced in a stainless steel dissolutor.
~) In about 1 litre of water is separately prepared a solution containing :
33.6 g of tromethamine +
53.3 g of N-(Methyl)-glucamine +
104.8 g of citric acid y) Once the above solution has been completely dissolved, it is added to the water in the dissolutor.
~) Under constant and slow stirring, 160.0 g of polyvinylpyrrolidone, 16.0 g of methyl p-hydroxybenzoate and 1.6 g of propyl p-hydroxybenzoate and, finally, the remaining quantity of citric acid (4.2 g) are added to yield the pH value of 4.6 to 6.0, which is adjusted, if necessary, by adding 0.1 N NaOH.
== 25 ~) Separately 6.4 106 I.U. of elcatonin are dissolved in about 20.0 ml of solution, resulting from step y) thus obtaining the mother solution.
Z) Under constant and slow stirring, the mother solution of elcatonin and the remaining ~uantity of water are added to the dissolutor to yield 16 Kg.
All manufacturing steps from ~) to ~) are carried out under nitrogen atmosphere at positive pressure.
CA 022l2~20 l997-08-07 W096/24370 - l6 - PCT/~l~GJ~31~6 The obtained solution is filtered for sterilization and subsequently bottled under nitrogen atmosphere at positive pressure according to the well-known methods in the Art.
Example 4 Stability study of calcitonin salmon nasal spray preparations of Examples l and 2 ' 10 The stability study is carried out comparing the pharmaceutical solution according to the invention of Examples l and 2 to two formulations available on the market, in order to assess the quality and the quantity of degradation products, during an interval of 18 months at the controlled storage temperature of +2~/+8~C.
Formulations I and II are those indicated in Examples l and 2, while the compared formulations III and IV have the following compositions:
Formulation III: l ml of solution containing 550 I.U. of calcitonin salmon as acetate salt, 0.002 g of glacial acetic acid, 0.002 g of sodium acetate trihydrate, 0.0075 g of sodium chloride and water for injectable preparations q.s. to l ml.
Formulation IV: l ml of solution containing 550 I.U. of calcitonin salmon as acetate salt, O.l mg of benzal-konium chloride, 8.5 mg of sodium chloride, 4 mg of O.l N
hydrochloric acid and 990.025 mg of bidistilled water.
CA 022l2520 l997-08-07 W096/24370 P~l/~l,'/00446 The obtained results are summarized in the following Table 1.
Table 1 ~IM~ 0 AFTBR
(Initial) 18 MONTH8 Formulation Degradation ~roduct~
hydroxy- dihydro- hydroxy- dihydro-calcitonin calcitonin calcitonin calcitonin % % % %
by weiqht by weiqht by weiqht by weight Formulation I 0.11 0 1. 87 0 (Example 1) Formulation II 0. 13 0 2.14 0 ~Example 2) Formulation III 0.10 0 4.31 2.58 Formulation IV 0.12 0 5.06 2.37 As it may be taken from the above results, the pharmaceutical formulations of the invention (I and II) generate, during the considered ageing period of 18 months, remarkably minor quantities of the degradation product hydroxy-calcitonin, compared to reference formulations III and IV which additionally produce another related substance indicated as dihydro-calcitonin (reduced calcitonin).
W096/24370 PCTI~l,5 Example 5 Comparative study of organoleptic characters of the pharmaceutical formulations I (according to the invention) and III (reference) of Example 4 In order to assess the tolerability and compliance of the considered preparations, a comparative double-blind study between the pharmaceutical formulation (according to the invention) and II (reference) of Example 4 has been carried out, by administering them to a total of 20 healthy and non smoking volunteers, divided into two groups.
In phase 1 test, lO volunteers have inhaled formulation I while the second group formulation III. Phase 2 test was carried out, after two hours interval, by administering to the first group formulation III and to the second group formulation I.
The obtained results are summarized in the following Tables 2 and 3.
Table 2 Phase 1 Test Organole~ticFormulation I Formulation III
evaluation Odour of acetic 0 7 acid Odourless 9 No difference 1 2 WO96/24370 P~ l,"JCISC
Table 3 Pha~e 2 Test - Organole~tic Formulation IFormulation III
e~aluation Odour of acetic 0 9 acid Odourless 8 0 No difference 2 It results from the above Tables 2 and 3 that most of the treated volunteers of the two groups (16) have reported that formulation III (reference) has a statistically significant unpleasant odour of acetic acid, while 17 volunteers have not detected any specific odour in formulation I (according to the invention).
2.10 mg/ml of tromethamine [c)]
6.82 mg/ml of citric acid td)]
CA 02212~20 1997-08-07 10.00 mg/ml of polyvinylpyrrolidone [e)]
1.00 mg/ml of methyl p-hydroxybenzoate tf)]
L
0.10 mg/ml of propyl p-hydroxybenzoate tf)]
976 . 65 mg/ml of water for injectable preparations.
The solutions according to the invention produce minimal degradation products, during the storage period. During an ageing period of 18 months they produce, a very reduced quantity of the inactive degradation product hydroxy-calcitonin. Advantageously the inventive solutions present, after 18 months of shelf-life, a 15 total quantity of degradation product substantially less than 5 ~ by weight limit indicated by various pharmacopoeias [Eur. Ph. II Ed., DAB 10 (1991), BP 88, FU IX Ed.] for calcitonin salmon substance. They are very suitable for endonasal administration, when dispensed in convenient well-known delivery system.
Another more particularly preferred embodiment according to the invention contains:
400 I.U./ml of elcatonin [a)]
3.33 mg/ml of N-(methyl)-~lucamine or glucamine [b)]
2.10 mg/ml of tromethamine lc)]
,.
6.82 mg/ml of citric acid ld)]
lo.00 mg/ml of polyvinylpyrrolidone te)]
1.00 mg/ml of methyl p-hydroxybenzoate [f)]
CA 022l2S20 l997-08-07 W096l24370 P~~ Oq~6 O.lO mg/ml of propyl p-hydroxybenzoate [f)]
976.65mg/ml of water for injectable preparations The surprising advantages of the pharmaceutical solutions according to the invention are summarized as follows:
A) The presence of citric acid [d)], which is useful to adjust the pH values to preferably from 4.6 to 6.0, allows the exact quantity of acetic acid, contained as volatile impurity in calcitonin salmon or in carbacalcitonin (elcatonin) to be determined specifically and precisely, by using conventional analytical methods described in several publications.
In fact, if acetic acid was added to the solution instead of citric acid, it would not be possible to determine, in the formulated preparation, the quantity of the volatile impurity acetic acid (maximum lS% by weight) contained in calcitonin salmon or in carbacalcitonin (elcatonin).
B) The solution according to the invention with citric acid [d)] is organoleptically more acceptable to patients who don't tolerate the unpleasant odour of acetic acid contained in some prior art compositions on the market.
C) Citric acid td)~ has been partially buffered, in the solutions according to the invention, preferably to pH 4.6 to 6.0, by using suitable concentrations of tromethamine [c)] and N-(methyl)glucamine or glucamine [b)] instead of sodium acetate, which can also develop a remarkable odour of acetic acid.
CA 02212~20 1997-08-07 D) Polyvinylpyrrolidone ranging from K15 to K120, te)]
is purposely included into the composition for endonasal administration, since surprisingly it is suitable to prolong the time of contact between the solution and the nasal mucosa for its binding properties.
E) In the solutions of the invention, the presence of preserving agents is optional, because the manufacturing process is carried out to obtain sterile formulations.
Moreover the'nasal bottles equipped with suitable pumps, characterized by absence of air introduction after actuation (dispensing the solution), eliminating, in this way the possible bacteria contamination, during usage. Therefore C1 4 alkylesters of p-hydroxybenzoic acid, particularly methyl p-hydroxybenzoate and/or propyl p-hydroxybenzoate, [f)] are introduced into the solutions of the invention only for additional protection, in case of an exceptional presence of bacteria.
F) More specifically for calcitonin salmon various pharmacopoeias fix an individual limit of 5 % by weight for each related substance {DAB (1991) "Verwandte Substanzen"; Eur. Ph. II Ed. "Substances apparentees";
BP 88 "Related substances"} for calcitonin salmon powder, as acetate salt, while other publications, more specifically Pharmaceutical Research Vol. 9, N. 11, 1992 ("Degradation of Synthetic Salmon Calcitonin Aqueous Solution" - Kang Choon Lee, Yoon Joong Lee, Hyun Myo Song, Chang Ju Chun and Patrick P. DeLuca) indicate that the degradation product is only the reduced calcitonin salmon (dihydro-calcitonin), when the solution presents an acidic pH. Now surprisingly it has been found that the solutions of the invention produce only minimal degradation product during the ageing period of storage.
CA 022l2~20 l997-08-07 W0 96/24370 ~ ;l ,C'~01 1C
The described embodiments of the invention may apply also to other natural or modified calcitonin, alike human calcitonin, eel calcitonin, carbacalcitonin (elcatonin), chicken calcitonin, porcine calcitonin.
The solutions according to the invention can be administered as drops, inhaler or spray, dispensed in suitable well known delivery systems.
The invention is further illustrated by the following examples.
Example l 15 Preparation of 38,461 bottles (1.0 ml) of calcitonin salmon nasal spray 100 I.U./actuation Each actuation dispensing 100 ~l of solution (100 I.U.
of active principle). 1 ml of the solution containing the following constituents:
Ingredient Amount Calcitonin salmon as acetate salt lx103 I.U.
Glucamine 3.33 mg Tromethamine 2.10 mg Citric acid (pH 4.6 to 6.0) 6.82 mg Polyvinylpyrrolidone 10.00 mg Methyl p-hydroxybenzoate 1.00 mg Propyl p-hydroxybenzoate 0.10 mg CA 02212~20 1997-08-07 W096/24370 PCT~6/00446 Water for injectable preparations 976.65 mg The manufacturing process is carried out with the - following conventional steps:
~) 34.0 kg of water for injectable preparations are introduced in a stainless steel dissolutor.
~) In about 3 litres of water is separately prepared a solution containing:
80.77 g of tromethamine +
128.1 g of glucamine +
250.1 g of citric acid y) Once the above solution has been completely dissolved, it is added to the water in the dissolutor.
~) Under constant and slow stirring, 384.61 g of polyvinylpyrrolidone, 38.461 g of methyl p-hydroxybenzoate and 3.846 g of propyl p-hydroxybenzoate and, finally, the remaining quantity of citric acid (12.2 g) are added to yield the pH value of 4.6 to 6.0, which is adjusted, if necessary, by adding 0.1 N NaOH.
~) Separately 38.461 x 106 I.U. of calcitonin salmon as acetate salt are dissolved in about 50 ml of solution, resulting from step y) thus obtaining the mother solution.
Z) Under constant and slow stirring, the mother - - solution of calcitonin salmon and the remaining quantity of water are added to the dissolutor to yield 38.461 kg.
CA 02212~20 1997-08-07 W096/24370 PCTi~~ 116 All manufacturing steps from ~) to ~) are carried out under nitrogen atmosphere at positive pressure.
The obtained solution is filtered for sterilization and subsequently bottled under nitrogen atmosphere at positive pressure according to the well-known methods in the Art.
Example 2 Preparation of 25,000 bottles (2.0 ml) of calcitonin salmon nasal spray 200 I.U:/actuation Each actuation dispensing lO0 ~l of solution (200 I.U.
of active principle). l ml of the solution containing the following constituents:
Ingredient Amount Calcitonin salmon as acetate salt 2x103 I.U.
N-(Methyl)-glucamine 3.33 mg Tromethamine 2.lO mg Citric acid (pH 4.6 to 6.0)6.82 mg Polyvinylpyrrolidone lO.00 mg Methyl p-hydroxybenzoatel.00 mg Propyl p-hydroxybenzoateO.lO mg Water for injectable preparations 976.65 mg CA 022l2~20 l997-08-07 W096/24370 PCT~G/C~~
The manufacturing process is carried out with the following conventional steps:
~) 45.0 kg of water for injectable preparations are introduced in a stainless steel dissolutor.
~) In about 3 litres of water a solution is separately prepared containing:
105.0 g of trometamine +
166.5 g of N-(methyl)-glucamine +
228.5 g of citric acid y) After the complete dissolution of the above solution it is added to the water in the dissolutor.
~) Under constant and slow stirring, 500.0 g of polyvinylpyrrolidone, 50.0 g of methyl p-hydroxybenzoate and 5.0 g of propyl p-hydroxybenzoate and, finally, the remaining quantity of citric acid (12.5 g) are added to yield the pH value of 4.6 to 6.0, which is adjusted, if necessary, by adding O.1 N NaOH.
~) Separately a mother solution of calcitonin salmon as acetate salt is prepared by dissolving l x 107 I.U. of this active principle in about 50 ml of solution resulting from step y).
~) Under constant and slow stirring, the mother solution of calcitonin salmon and the remaining quantity of water are added to the dissolutor to yield 50 kg.
CA 022l2~20 l997-08-07 W096/24370 PCT/~GIC~1~C
All manufacturing steps from ~) to ~) are carried out under nitrogen atmosphere at positive pressure.
The obtained solution is sterilized and bottled under nitrogen atmosphere at positive pressure according to the well-known methods in the Art.
Example 3 Preparation of lO,OOO bottles (l.6 ml) of carbacalcitonin (elcatonin) nasal spray 40 I.U./actuation.
Each actuation dispensing lOO ~l of solution (40 .U. of lS active principle).
l ml of the solution containing the following constituents:
Ingredient Amount Elcatonin 400 I.U.
N-(Methyl)-glucamine 3.33 mg Tromethamine 2.lO mg Citric acid (pH 4.6 to 6.0)6.82 mg Polyvinylpyrrolidone lO.OO mg Methyl p-hydroxybenzoatel.OO mg Propyl p-hydroxybenzoateO.lO mg Water for injectable preparations 976.65 mg - - -CA 02212~20 l997-08-07 W096/24370 PCT/~l~C/~516 The manufacturing process is carried out with the following conventional steps :
- ~) 13.5 Kg of water for injectable preparations are introduced in a stainless steel dissolutor.
~) In about 1 litre of water is separately prepared a solution containing :
33.6 g of tromethamine +
53.3 g of N-(Methyl)-glucamine +
104.8 g of citric acid y) Once the above solution has been completely dissolved, it is added to the water in the dissolutor.
~) Under constant and slow stirring, 160.0 g of polyvinylpyrrolidone, 16.0 g of methyl p-hydroxybenzoate and 1.6 g of propyl p-hydroxybenzoate and, finally, the remaining quantity of citric acid (4.2 g) are added to yield the pH value of 4.6 to 6.0, which is adjusted, if necessary, by adding 0.1 N NaOH.
== 25 ~) Separately 6.4 106 I.U. of elcatonin are dissolved in about 20.0 ml of solution, resulting from step y) thus obtaining the mother solution.
Z) Under constant and slow stirring, the mother solution of elcatonin and the remaining ~uantity of water are added to the dissolutor to yield 16 Kg.
All manufacturing steps from ~) to ~) are carried out under nitrogen atmosphere at positive pressure.
CA 022l2~20 l997-08-07 W096/24370 - l6 - PCT/~l~GJ~31~6 The obtained solution is filtered for sterilization and subsequently bottled under nitrogen atmosphere at positive pressure according to the well-known methods in the Art.
Example 4 Stability study of calcitonin salmon nasal spray preparations of Examples l and 2 ' 10 The stability study is carried out comparing the pharmaceutical solution according to the invention of Examples l and 2 to two formulations available on the market, in order to assess the quality and the quantity of degradation products, during an interval of 18 months at the controlled storage temperature of +2~/+8~C.
Formulations I and II are those indicated in Examples l and 2, while the compared formulations III and IV have the following compositions:
Formulation III: l ml of solution containing 550 I.U. of calcitonin salmon as acetate salt, 0.002 g of glacial acetic acid, 0.002 g of sodium acetate trihydrate, 0.0075 g of sodium chloride and water for injectable preparations q.s. to l ml.
Formulation IV: l ml of solution containing 550 I.U. of calcitonin salmon as acetate salt, O.l mg of benzal-konium chloride, 8.5 mg of sodium chloride, 4 mg of O.l N
hydrochloric acid and 990.025 mg of bidistilled water.
CA 022l2520 l997-08-07 W096/24370 P~l/~l,'/00446 The obtained results are summarized in the following Table 1.
Table 1 ~IM~ 0 AFTBR
(Initial) 18 MONTH8 Formulation Degradation ~roduct~
hydroxy- dihydro- hydroxy- dihydro-calcitonin calcitonin calcitonin calcitonin % % % %
by weiqht by weiqht by weiqht by weight Formulation I 0.11 0 1. 87 0 (Example 1) Formulation II 0. 13 0 2.14 0 ~Example 2) Formulation III 0.10 0 4.31 2.58 Formulation IV 0.12 0 5.06 2.37 As it may be taken from the above results, the pharmaceutical formulations of the invention (I and II) generate, during the considered ageing period of 18 months, remarkably minor quantities of the degradation product hydroxy-calcitonin, compared to reference formulations III and IV which additionally produce another related substance indicated as dihydro-calcitonin (reduced calcitonin).
W096/24370 PCTI~l,5 Example 5 Comparative study of organoleptic characters of the pharmaceutical formulations I (according to the invention) and III (reference) of Example 4 In order to assess the tolerability and compliance of the considered preparations, a comparative double-blind study between the pharmaceutical formulation (according to the invention) and II (reference) of Example 4 has been carried out, by administering them to a total of 20 healthy and non smoking volunteers, divided into two groups.
In phase 1 test, lO volunteers have inhaled formulation I while the second group formulation III. Phase 2 test was carried out, after two hours interval, by administering to the first group formulation III and to the second group formulation I.
The obtained results are summarized in the following Tables 2 and 3.
Table 2 Phase 1 Test Organole~ticFormulation I Formulation III
evaluation Odour of acetic 0 7 acid Odourless 9 No difference 1 2 WO96/24370 P~ l,"JCISC
Table 3 Pha~e 2 Test - Organole~tic Formulation IFormulation III
e~aluation Odour of acetic 0 9 acid Odourless 8 0 No difference 2 It results from the above Tables 2 and 3 that most of the treated volunteers of the two groups (16) have reported that formulation III (reference) has a statistically significant unpleasant odour of acetic acid, while 17 volunteers have not detected any specific odour in formulation I (according to the invention).
Claims (23)
1. Pharmaceutical non inorganic saline solutions for endonasal administration comprising a) a natural or modified calcitonin, preferably salmon or alternatively carbacalcitonin (elcatonin), or its pharmaceutically acceptable salts, characterized in that it further comprise the following organic excipients b) N-(methyl)-glucamine or glucamine, c) tromethamine, d) citric acid, and e) polyvinylpyrrolidone ranging from K15 to K120.
2. Pharmaceutical solutions according to claim 1, characterized in that the calcitonin is human calcitonin, eel calcitonin, carbacalcitonin (elcatonin), chicken calcitonin or porcine calcitonin.
3. Pharmaceutical solutions according to claim 1 or claim 2, characterized in that the polyvinyl-pyrrolidone is of the type K40.
4. Pharmaceutical solutions according to any one of claims 1 to 3, characterized in that they comprise:
a) the natural or modified calcitonin or its pharmaceutically acceptable salts in concentrations of 250 I.U./ml to 5.000 I.U./ml, b) the N-(methyl)-glucamine or glucamine in concentrations of 2.0 to 5.0 mg/ml, c) the tromethamine in concentrations of 1.0 to 4.0 mg/ml, d) the citric acid in concentrations of 5.0 to 9.0 mg/ml, and e) the polyvinylpyrrolidone ranging from K15 to K120 in concentrations of 5 to 25 mg/ml.
a) the natural or modified calcitonin or its pharmaceutically acceptable salts in concentrations of 250 I.U./ml to 5.000 I.U./ml, b) the N-(methyl)-glucamine or glucamine in concentrations of 2.0 to 5.0 mg/ml, c) the tromethamine in concentrations of 1.0 to 4.0 mg/ml, d) the citric acid in concentrations of 5.0 to 9.0 mg/ml, and e) the polyvinylpyrrolidone ranging from K15 to K120 in concentrations of 5 to 25 mg/ml.
5. Pharmaceutical solutions according to any one of claims 1 to 4, characterized in that the concentration of the natural or modified calcitonin or its pharmaceutically acceptable salts is from 400 I.U. to 1,200 I.U./ml.
6. Pharmaceutical solutions according to any one of claims 1 to 5, characterized in that the concentration of the N-(methyl)-glucamine or glucamine is from 2.5 to 4.0 mg/ml.
7. Pharmaceutical solutions according to any one of claims 1 to 6, characterized in that the concentration of tromethamine is from 1.5 to 2.5 mg/ml.
8. Pharmaceutical solutions according to any one of claims 1 to 7, characterized in that the concentration of the citric acid is from 6.0 to 8.0 mg/ml.
9. Pharmaceutical solutions according to any one of claims 1 to 8, characterized in that the concentration of the polyvinylpyrrolidone ranging from K15 to K120 is from 8 to 15 mg/ml.
10. Pharmaceutical solutions according to any one of claims 1 to 9, characterized in that they are sterile formulations.
11. Pharmaceutical solutions according to any one of claims 1 to 10, characterized in that they also contain 1 or more C1-4 alkylesters of p-hydroxybenzoic acid for additional protection.
12. Pharmaceutical solutions according to any one of claims 1 to 11, characterized in that the C1-4 alkylesters of p-ydroxybenzoic acid is methyl p-hydroxy benzoate and/or propyl p-hydroxy benzoate.
13. Pharmaceutical solutions according to any one of claims 1 to 12, characterized in that they have pH values preferably of from 4.6 to 6Ø
14. Pharmaceutical solutions according to any one of claims 1 to 13, characterized in that they have pH values preferably of from 5.0 to 5.9.
15. Pharmaceutical solutions according to any one of claims 1 to 14, characterized in that they comprise:
1x10 3 I.U./ml of calcitonin salmon as acetate salt 3.33 mg/ml of N-(methyl)-glucamine or glucamine 2.10 mg/ml of tromethamine 6.82 mg/ml of citric acid 10.00 mg/ml of polyvinylpyrrolidone 1.00 mg/ml of methyl p-hydroxy benzoate 0.10 mg/ml of propyl p-hydroxy benzoate 976.65 mg/ml of water for injectable preparations
1x10 3 I.U./ml of calcitonin salmon as acetate salt 3.33 mg/ml of N-(methyl)-glucamine or glucamine 2.10 mg/ml of tromethamine 6.82 mg/ml of citric acid 10.00 mg/ml of polyvinylpyrrolidone 1.00 mg/ml of methyl p-hydroxy benzoate 0.10 mg/ml of propyl p-hydroxy benzoate 976.65 mg/ml of water for injectable preparations
16. Pharmaceutical solutions according to any one of claims 1 to 15, characterized in that they conprise 2x103 I.U./ml of calcitonin salmon as acetate salt 3.33 mg/ml of N-(methyl)-glucamine or glucamine 2.10 mg/ml of tromethamine 6.82 mg/ml of citric acid 10.00 mg/ml of polyvinylpyrrolidone 1.00 mg/ml of methyl p-hydroxy benzoate 0.10 mg/ml of propyl p-hydroxy benzoate 976.65 mg/ml of water for injectable preparations
17. Pharmaceutical solutions according to any one of claims 1 to 16, characterized in that they comprise:
400 I.U./ml of elcatonin 3.33 mg/ml of N-(methyl)-glucamine 2.10 mg/ml of tromethamine 6.82 mg/ml of citric acid 10.00 mg/ml of polyvinylpyrrolidone 1.00 mg/ml of methyl p-hydroxy benzoate 0.10 mg/ml of propyl p-hydroxy benzoate 976.65 mg/ml of water for injectable preparations
400 I.U./ml of elcatonin 3.33 mg/ml of N-(methyl)-glucamine 2.10 mg/ml of tromethamine 6.82 mg/ml of citric acid 10.00 mg/ml of polyvinylpyrrolidone 1.00 mg/ml of methyl p-hydroxy benzoate 0.10 mg/ml of propyl p-hydroxy benzoate 976.65 mg/ml of water for injectable preparations
18. Pharmaceutical solutions according to any one of claims 1 to 17, having enhanced organoleptic character.
19. Pharmaceutical solutions according to any one of claims 1 to 18, characterized in that the polyvinylpyrrolidone prolongs the time of contact between the solution and the nasal mucosa.
20. Pharmaceutical solutions, according to any one of claims 1 to 19, comprising salmon calcitonin, characterized in that the solutions produce, during 18 months storage, very little hydroxy-calcitonin.
21. Pharmaceutical solutions according to any one of claims 1 to 20, comprising salmon calcitonin characterized in that the solutions present, during 18 months storage, substantially less than the 5 wt % degradation products indicated for each impurity (related substance) by various pharmacopoeias [Eur. Ph. II Ed., DAB 10 (1991), BP 88, FU IX Ed.] for calcitonin salmon substance.
22. Pharmaceutical solutions according to any one of claims 1 to 21, characterized in that they are suitable for endonasal administration.
23. Use of pharmaceutical solutions according to any one of claims 1 to 22 for use in conventional analytical methods to determine the quantity of acetic acid contained, as volatile impurity, in calcitonin salmon active ingredient or any other natural or modified calcitonin as acetate used for their preparation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP95101681.5 | 1995-02-08 | ||
| EP95101681A EP0726075A1 (en) | 1995-02-08 | 1995-02-08 | Pharmaceutical non-inorganic saline solutions for endonasal administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2212520A1 true CA2212520A1 (en) | 1996-08-15 |
Family
ID=8218965
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002210664A Abandoned CA2210664A1 (en) | 1995-02-08 | 1996-02-02 | Calcitonin salmon analogues, their preparation, medicinal use and use as analytical agents |
| CA002212520A Abandoned CA2212520A1 (en) | 1995-02-08 | 1996-02-08 | Pharmaceutical non inorganic saline solutions for endonasal administration of a calcitonin |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002210664A Abandoned CA2210664A1 (en) | 1995-02-08 | 1996-02-02 | Calcitonin salmon analogues, their preparation, medicinal use and use as analytical agents |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US6107277A (en) |
| EP (3) | EP0726075A1 (en) |
| JP (2) | JPH11506416A (en) |
| KR (2) | KR100430101B1 (en) |
| AT (2) | ATE191719T1 (en) |
| AU (2) | AU4787996A (en) |
| BR (1) | BR9607410A (en) |
| CA (2) | CA2210664A1 (en) |
| DE (4) | DE726075T1 (en) |
| ES (2) | ES2146869T3 (en) |
| GB (1) | GB9523442D0 (en) |
| HU (1) | HUP9600266A3 (en) |
| PE (1) | PE28397A1 (en) |
| PL (1) | PL183398B1 (en) |
| PT (2) | PT809654E (en) |
| WO (2) | WO1996024618A1 (en) |
| ZA (2) | ZA96779B (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE726075T1 (en) * | 1995-02-08 | 1996-12-12 | Therapicon Srl | Non-inorganic pharmaceutical saline solutions for endonasal administration |
| US6034064A (en) * | 1995-04-07 | 2000-03-07 | Hoechst Pharmaceuticals & Chemicals K.K. | Peptides and therapeutic agent for autoimmune diseases containing the same |
| DE19653969A1 (en) * | 1996-12-20 | 1998-06-25 | Boehringer Ingelheim Kg | New aqueous pharmaceutical preparation for the production of propellant-free aerosols |
| IT1298780B1 (en) * | 1998-03-24 | 2000-02-02 | Therapicon Srl | Pharmaceutical compositions for parenteral use are based on aqueous solutions of natural or synthetic calcitonine |
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-
1995
- 1995-02-08 DE DE0726075T patent/DE726075T1/en active Pending
- 1995-02-08 EP EP95101681A patent/EP0726075A1/en not_active Withdrawn
- 1995-11-15 GB GBGB9523442.3A patent/GB9523442D0/en active Pending
-
1996
- 1996-02-01 ZA ZA96779A patent/ZA96779B/en unknown
- 1996-02-02 KR KR1019970705486A patent/KR100430101B1/en not_active IP Right Cessation
- 1996-02-02 ZA ZA96835A patent/ZA96835B/en unknown
- 1996-02-02 ES ES96903997T patent/ES2146869T3/en not_active Expired - Lifetime
- 1996-02-02 EP EP96903997A patent/EP0809654B1/en not_active Expired - Lifetime
- 1996-02-02 AT AT96903997T patent/ATE191719T1/en not_active IP Right Cessation
- 1996-02-02 PT PT96903997T patent/PT809654E/en unknown
- 1996-02-02 AU AU47879/96A patent/AU4787996A/en not_active Abandoned
- 1996-02-02 DE DE29622959U patent/DE29622959U1/en not_active Expired - Lifetime
- 1996-02-02 DE DE69607749T patent/DE69607749T2/en not_active Expired - Fee Related
- 1996-02-02 CA CA002210664A patent/CA2210664A1/en not_active Abandoned
- 1996-02-02 WO PCT/EP1996/000487 patent/WO1996024618A1/en active IP Right Grant
- 1996-02-02 JP JP8523975A patent/JPH11506416A/en not_active Ceased
- 1996-02-05 KR KR1019960002720A patent/KR100397034B1/en not_active IP Right Cessation
- 1996-02-07 PL PL96312683A patent/PL183398B1/en not_active IP Right Cessation
- 1996-02-07 HU HU9600266A patent/HUP9600266A3/en unknown
- 1996-02-07 JP JP02092496A patent/JP4123309B2/en not_active Expired - Fee Related
- 1996-02-08 PE PE1996000091A patent/PE28397A1/en not_active Application Discontinuation
- 1996-02-08 PT PT96903969T patent/PT809512E/en unknown
- 1996-02-08 AU AU47863/96A patent/AU4786396A/en not_active Abandoned
- 1996-02-08 CA CA002212520A patent/CA2212520A1/en not_active Abandoned
- 1996-02-08 AT AT96903969T patent/ATE215381T1/en not_active IP Right Cessation
- 1996-02-08 BR BR9607410A patent/BR9607410A/en not_active IP Right Cessation
- 1996-02-08 DE DE69620393T patent/DE69620393T2/en not_active Expired - Lifetime
- 1996-02-08 ES ES96903969T patent/ES2173267T3/en not_active Expired - Lifetime
- 1996-02-08 EP EP96903969A patent/EP0809512B1/en not_active Expired - Lifetime
- 1996-02-08 WO PCT/EP1996/000446 patent/WO1996024370A1/en active IP Right Grant
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1997
- 1997-08-08 US US08/907,602 patent/US6107277A/en not_active Expired - Fee Related
- 1997-08-08 US US08/908,986 patent/US6087338A/en not_active Expired - Fee Related
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