WO1988000829A1 - Pharmaceutical compositions containing a bisphosphonate and their use for nasal administration - Google Patents
Pharmaceutical compositions containing a bisphosphonate and their use for nasal administration Download PDFInfo
- Publication number
- WO1988000829A1 WO1988000829A1 PCT/DK1987/000084 DK8700084W WO8800829A1 WO 1988000829 A1 WO1988000829 A1 WO 1988000829A1 DK 8700084 W DK8700084 W DK 8700084W WO 8800829 A1 WO8800829 A1 WO 8800829A1
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- Prior art keywords
- acid
- hydroxy
- bisphosphonic acid
- nasal
- bisphosphonate
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Classifications
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
Definitions
- compositions containing a bisphosphonate and their use for nasal administration are provided.
- the present invention relates to new pharmaceutical compositions containing a bisphosphonate and their use for the nasal administration to patients suffering from diseases where treatment with a bisphosphonate is indicated.
- Bisphosphonates are drugs which can be used in certain diseases involving calcium metabolism, such as Paget's disease, hypercalcaemia due to malignancy, osteoporosis and rheumatoid arthritis.
- Bisphosphonates have hitherto been administered either orally or intravenously to patients.
- the oral absorption is poor and often accompanied by gastro ⁇ intestinal side effects.
- the degree of absorption shows substantial individual variations. Consequently, intravenous administration has up till now had to be used whenever a rapid and reliable delivery of bisphosphonates was needed.
- penetration enhancers can be used to improve the nasal absorption of compounds of higher molecular weight, such as insulin, glucagon and calcitonin, but it was not to be expected that such enhancers would be able to improve the absorption of compounds of relatively low molecular weight like bisphosphonates.
- Any bisphosphonic acid or salt thereof suitable for treatment of patients can form part of the pharmaceutical compositions according to the present invention.
- bisphosphonic acids mention may be made of l-hydroxy-alkylidene-l,l-bisphosphonic acids, e.g.
- the bisphosphonic acids are tetrabasic acids which can form mono-, di-, tri- and tetra-salts with bases.
- the bisphosphonic acids are preferably being used in the form of neutral salts with pharmaceutically acceptable bases.
- Suitable enhancers for the nasal absorption of bisphosphonates include, but are not limited to, compounds of the general formula I:
- X in the o- or ⁇ -position
- Y in the o- or ⁇ -position
- Y in the o- or ⁇ -position
- R stands for -OH or -NHZ, and in which the dotted lines indicate the possibility of double bond(s); when R represents -NHZ, then Z stands for alkyl or aryl, substituted with carboxyl, sulfonic acid groups, and/or quaternary ammonium groups; or compounds of the general formula II:
- R , R , and R in the o- or ⁇ -position, which can be the same or different, each stands for hydrogen or -OH, and in which R has the same meaning as in formula I, provided that not all R , R , R can be hydrogen at
- the pharmaceutical composition of the present invention is formed into a nasal preparation.
- the physiologically active bisphosphonate is contained as the drug, optionally together with an absorption enhancer.
- the nasal preparation according to the present invention can be produced by conventional processes. For example, small amounts of a pH adjusting agent, preservative, thickening agent (natural gums, cellulose derivatives, acrylic acid polymers, vinyl polymers etc.) and/or excipients are incorporated.
- the nasal preparation of the present invention may take a solid, liquid or semi-liquid form.
- a solid form the above components may be simply blended or be freeze-dried to provide a powdery composition, the preferred particle size in either case being about 20 to 250 ⁇ .
- a liquid preparation it is preferably an aqueous solution, an aqueous suspension or an oil suspension.
- the semi-solid preparation is preferably an aqueous or oleaginous gel or ointment.
- the content of bisphosphonate in the final preparation is about 0.005 to 50 w/v% and preferably about 0.01 to 30 w/v% and the optional content of absorption 5 enhancer is from 0 to 5 w/v%, preferably from 0 to 1 w/v%.
- the amount of bisphosphonate in the preparation is about 0.001 to 50 w/v% and preferably about 0.05 to 40 w/v%, and the optional content of absorption enhancer is from 0 to 5 ° w/v%, preferably from 0 to 1 w/v%.
- the excipient is exemplified by glucose, mannitol, inositol, sucrose, lactose, fructose, starch, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hydroxy- propylmethyl cellulose, polyvinylpyrrolidone, etc.
- the liquid preparation can be produced by known procedure.
- an aqueous preparation for nasal administration can be produced by dissolving, suspending or emulsifying the active components in water, a buffer solution or an aqueous medium.
- the oil suspension for nasal use can be produced by suspending or emulsifying the active components in an oleaginous base.
- the above mentioned oleaginous basis is examplified by various oils and fats such as sesame oil, olive oil, corn oil, soybean oil, cotton seed oil, peanut oil, lanoline, vaseline, paraffin, coparaffinate, silicone oil, glycerol fatty acid having 6 to 30 carbon atoms or its glycerol ester or its alcoholic ester, or a mixture thereof.
- oils and fats such as sesame oil, olive oil, corn oil, soybean oil, cotton seed oil, peanut oil, lanoline, vaseline, paraffin, coparaffinate, silicone oil, glycerol fatty acid having 6 to 30 carbon atoms or its glycerol ester or its alcoholic ester, or a mixture thereof.
- an aqueous or oleaginous gel or ointment can be produced by the per se conventional procedure.
- an aqueous gel for nasal administration can be produced in the following manner. First, an aqueous solution or suspension of the active components is prepared and, if required, a pH adjusting agent, a preservative and/or the like are added. The solution is divided into halves and an aqueous gel base is dissolved or dispersed in one of the halves and heated or cooled to give a stable gel. The two halves are combined and evenly mixed to give an aqueous gel preparation.
- Adjustment of the pH of the preparation can be effected by adding an acid, a base, a buffer solution or the like in the course of the production of the preparation.
- the acid there may be mentioned inorganic acids (like hydrochloric acid, boric acid, phosphoric acid, carbonic acid, etc), amino acids and organic acids (e.g. monocarboxylic acids, oxycarboxylic acids, polycarboxylic acids).
- the base is exemplified by sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate etc.
- aqueous gel basis examples include natural gums (e.g. gum tragacanth, gum acasia, gum karaya, Irish moss, gum guaiac, gum xanthane, locust bean gum etc) , cellulose derivati es (e.g. methylcellulose, carboxymethylcellulose etc), acrylic acid polymers (e.g. polyacrylic acid, polymethacrylic acid etc) , vinyl polymers (e.g. polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, carboxypolymethylene etc) , synthetic polysaccharides (e.g. polysucrose, polyglucose, polylactose etc), starch, dextrin, pectin, sodium alginate etc. These bases may be used in the form of appropriate mixtures of two or more species.
- natural gums e.g. gum tragacanth, gum acasia, gum karaya, Irish mos
- the oleaginous ointment for nasal administration can be produced by dispersing the active components evenly in a hot melt of an oleaginous base and cooling the same under stirring.
- the oleaginous- base may be one of those mentioned hereinbefore.
- Preservatives may be incorporated in nasal preparations.
- preservatives include phenolic compounds such as phenol, cresol etc; alcohols such as chlorobutanol, phenylethyl alcohol, propylene glycol etc; invert soaps such as benzalkoniu chloride, benzethonium chloride etc; benzoic acid, sorbic acid, dehydroacetic acid and sulfurous acid and salts thereof; acids and their salts such as sodium hydrogen sulfite.
- the nasal preparation of the invention is in solid form, it can be administered in the following exemplary way.
- a capsule containing the powdery preparation is set in an exclusive dust applicator equipped with needles to pierce the capsule at the top and bottom thereof and an air balloon is used to drive the powdery contents into the nasal cavity.
- a liquid preparation In the case of a liquid preparation, it is put into a nasal douche, an atomizer or a spray-mist applicator suited for nasal application of liquids and dripped or sprayed into the nasal cavity.
- the semi-solid preparation can be administered, for example by filling a tube with the preparation and sending the preparation directly into the nasal cavity through an applicator attached to the mouth of the tube or by administering the indicated dose of the preparation by means of a nasal insertion device.
- the proper amount of the solid preparation per dose is about 5 mg to 100 mg, that of the liquid preparation is about 0.05 to 0.5 ml, and that of the semi-solid preparation is about 50 mg to 500 mg.
- the nasal preparation may be administered from one to about four times per day.
- the invention also relates to a method for treating patients suffering from a disease where treatment with a bisphosphonate is indicated, such as Paget's disease, hyper- calcaemia due to malignancy, osteoporosis and rheumatoid arthritis, said treatment consisting of administering to the patient in need of treatment an effective amount of the present composition.
- the final solution was diluted with water to a total volume of 100 ml.
- Preparation II was sprayed into the nasal cavity of 2 dogs. Preparation I was given either orally, intravenously or nasally (as a spray) to the same two dogs. Urine (0 - 24 hours) was collected in all four experiments and the urinary excretion of EB 899 was determined analytically.
- Example 2 The following preparation may be used for the nasal administration of the disodium salt of 3-amino-l-hydroxy- propylidene-1,1-bisphosphonic acid (APD) either as drops or as a spray:
- APD 3-amino-l-hydroxy- propylidene-1,1-bisphosphonic acid
- Example 3 For the nasal administration of 3-(N,N-dimethylamino)- -l-hydroxy-propylidene-l,l-bisphosphonic acid, the following preparation may be used:
Abstract
Pharmaceutical compositions containing a bisphosphonate or a salt thereof, optionally together with an enhancer for nasal absorption, and their use for nasal administration. The enhancer for the nasal absorption preferably is sodium tauro-24,25-dihydrofusidate (STDF).
Description
Pharmaceutical compositions containing a bisphosphonate and their use for nasal administration
1.
The present invention relates to new pharmaceutical compositions containing a bisphosphonate and their use for the nasal administration to patients suffering from diseases where treatment with a bisphosphonate is indicated.
Bisphosphonates (or diphosphonates) are drugs which can be used in certain diseases involving calcium metabolism, such as Paget's disease, hypercalcaemia due to malignancy, osteoporosis and rheumatoid arthritis.
Bisphosphonates have hitherto been administered either orally or intravenously to patients. However, the oral absorption is poor and often accompanied by gastro¬ intestinal side effects. Furthermore, the degree of absorption shows substantial individual variations. Consequently, intravenous administration has up till now had to be used whenever a rapid and reliable delivery of bisphosphonates was needed.
Thus, there is a need for a suitable way of administering bisphosphonates enterally, but despite the fact that this problem has existed for more than a decade, no solution has been found. It has now surprisingly turned out that in spite of their very polar nature it is possible to administer bisphosphonates through the nasal route, thereby not only avoiding the side effects encountered with oral administration, but even obtaining a degree of absorption which is several times higher than that obtained after oral administration.
It has further turned out that the addition of penetration enhancers to the pharmaceutical preparation
intended for nasal administration improves the absorption of some bisphosphonates dramatically. It is known (European patent application, publication No. 128831) that penetration enhancers can be used to improve the nasal absorption of compounds of higher molecular weight, such as insulin, glucagon and calcitonin, but it was not to be expected that such enhancers would be able to improve the absorption of compounds of relatively low molecular weight like bisphosphonates. Any bisphosphonic acid or salt thereof suitable for treatment of patients can form part of the pharmaceutical compositions according to the present invention. As examples of such bisphosphonic acids, mention may be made of l-hydroxy-alkylidene-l,l-bisphosphonic acids, e.g. l-hydroxy-ethylidene-l,l-bisphosphonic acid (etidronate) or l-hydroxy-pentylidene-l,l-bisphosphonic acid; dichloro ethylene-bisphosphonic acid (clodronate) ; difluoromethylene-bisphosphonic acid; 3-amino-l-hydroxy-propylidene-l,l-bisphophonic acid (APD) ; 3-(N,N-dimethylamino)-l-hydroxy-propylidene-l,l-bis- phosphonic acid;
3-(N,N-diethylamino)-l-hydroxy-propylidene-l,l-bisphosphonic acid; 4-amino-l-hydroxy-butylidene-1,1- isphosphonic acid; 4-(N,N-dimethylamino)-l-hydroxy-butylidene-l,l-bisphosphonic acid;
5-amino-l-hydroxy-pentylidene-l,l-bisphosphonic acid; 6-amino-l-hydroxy-hexylidene-l,1-bisphosphonic acid; , 2-(2*-pyridyl)-ethylidene-l,l-bisphosphonic acid; N-(3'-methyl-2'-pyridyl)-aminomethylene isphosphonic acid; (4-chlorophenylthiomethylene)-bisphophonic acid (SR 41319); compounds described and claimed in international patent application PCT/DK85/00071 filed on July 25, 1985 (claiming priority from British patent application No. 8419489, filed on July 31, 1984); and compounds described and claimed in international patent application PCT/DK86/00132 filed on December 10, 1986 (claiming priority from British patent application No. 8530603, filed on December 12, 1985).
The bisphosphonic acids are tetrabasic acids which can form mono-, di-, tri- and tetra-salts with bases. In the compositions of the present invention, the bisphosphonic acids are preferably being used in the form of neutral salts with pharmaceutically acceptable bases.
Examples of suitable enhancers for the nasal absorption of bisphosphonates include, but are not limited to, compounds of the general formula I:
in which X (in the o- or β-position) stands for hydrogen, OH-, -O-alkyl, -O-acyl, -S-alkyl, -S-acyl or halogen; Y (in the o- or β-position) stands for -OH, -O-alkyl, -O-acyl, halogen, -O-alkylsulfonyl, -O-arylsulfonyl; R stands for -OH or -NHZ, and in which the dotted lines indicate the possibility of double bond(s); when R represents -NHZ, then Z stands for alkyl or aryl, substituted with carboxyl, sulfonic acid groups, and/or quaternary ammonium groups; or compounds of the general formula II:
wherein R , R , and R (in the o- or β-position), which can be the same or different, each stands for hydrogen or -OH, and in which R has the same meaning as in formula I, provided that not all R , R , R can be hydrogen at
__L _b ___ the same time. The compounds of formula I and II are preferably used in the form of pharmaceutically acceptable salts.
The pharmaceutical composition of the present invention is formed into a nasal preparation.
In the nasal preparation, the physiologically active bisphosphonate is contained as the drug, optionally together with an absorption enhancer.
The nasal preparation according to the present invention can be produced by conventional processes. For example, small amounts of a pH adjusting agent, preservative, thickening agent (natural gums, cellulose derivatives, acrylic acid polymers, vinyl polymers etc.) and/or excipients are incorporated.
The nasal preparation of the present invention may take a solid, liquid or semi-liquid form. In the case of a solid form, the above components may be simply blended or be freeze-dried to provide a powdery composition, the preferred particle size in either case being about 20 to 250μ. In the case of a liquid preparation, it is preferably an aqueous solution, an aqueous suspension or an oil suspension. The semi-solid preparation is preferably an aqueous or oleaginous gel or ointment.
As to the proportion of each component in the nasal preparation, the content of bisphosphonate in the final preparation is about 0.005 to 50 w/v% and preferably about 0.01 to 30 w/v% and the optional content of absorption 5 enhancer is from 0 to 5 w/v%, preferably from 0 to 1 w/v%. In the case of a liquid or semi-liquid preparation, the amount of bisphosphonate in the preparation is about 0.001 to 50 w/v% and preferably about 0.05 to 40 w/v%, and the optional content of absorption enhancer is from 0 to 5 ° w/v%, preferably from 0 to 1 w/v%.
The excipient is exemplified by glucose, mannitol, inositol, sucrose, lactose, fructose, starch, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hydroxy- propylmethyl cellulose, polyvinylpyrrolidone, etc. The liquid preparation can be produced by known procedure. For example, an aqueous preparation for nasal administration can be produced by dissolving, suspending or emulsifying the active components in water, a buffer solution or an aqueous medium. The oil suspension for nasal use can be produced by suspending or emulsifying the active components in an oleaginous base.
The above mentioned oleaginous basis is examplified by various oils and fats such as sesame oil, olive oil, corn oil, soybean oil, cotton seed oil, peanut oil, lanoline, vaseline, paraffin, coparaffinate, silicone oil, glycerol fatty acid having 6 to 30 carbon atoms or its glycerol ester or its alcoholic ester, or a mixture thereof.
As to the semi-solid preparation, an aqueous or oleaginous gel or ointment can be produced by the per se conventional procedure. For example, such an aqueous gel for nasal administration can be produced in the following manner. First, an aqueous solution or suspension of the active components is prepared and, if required, a pH adjusting agent, a preservative and/or the like are added. The solution is divided into halves and an aqueous gel base is dissolved or dispersed in one of the halves and heated or cooled to give a stable gel. The two halves are combined and evenly mixed to give an aqueous gel preparation.
Adjustment of the pH of the preparation can be effected by adding an acid, a base, a buffer solution or the like in the course of the production of the preparation. As examples of the acid, there may be mentioned inorganic acids (like hydrochloric acid, boric acid, phosphoric acid, carbonic acid, etc), amino acids and organic acids (e.g. monocarboxylic acids, oxycarboxylic acids, polycarboxylic acids). The base is exemplified by sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate etc.
Examples of the aqueous gel basis include natural gums (e.g. gum tragacanth, gum acasia, gum karaya, Irish moss, gum guaiac, gum xanthane, locust bean gum etc) , cellulose derivati es (e.g. methylcellulose, carboxymethylcellulose etc), acrylic acid polymers (e.g. polyacrylic acid, polymethacrylic acid etc) , vinyl polymers (e.g. polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, carboxypolymethylene etc) , synthetic polysaccharides (e.g. polysucrose, polyglucose, polylactose etc), starch, dextrin, pectin, sodium alginate etc. These bases may be used in the form of appropriate mixtures of two or more species.
The oleaginous ointment for nasal administration can be produced by dispersing the active components evenly in a hot melt of an oleaginous base and cooling the same under stirring. The oleaginous- base may be one of those mentioned hereinbefore.
Preservatives may be incorporated in nasal preparations. Examples of such preservatives include phenolic compounds such as phenol, cresol etc; alcohols such as chlorobutanol, phenylethyl alcohol, propylene glycol etc; invert soaps such as benzalkoniu chloride, benzethonium chloride etc; benzoic acid, sorbic acid, dehydroacetic acid and sulfurous acid and salts thereof; acids and their salts such as sodium hydrogen sulfite. If the nasal preparation of the invention is in solid form, it can be administered in the following exemplary way. A capsule containing the powdery preparation is set in an exclusive dust applicator equipped with needles to pierce
the capsule at the top and bottom thereof and an air balloon is used to drive the powdery contents into the nasal cavity.
In the case of a liquid preparation, it is put into a nasal douche, an atomizer or a spray-mist applicator suited for nasal application of liquids and dripped or sprayed into the nasal cavity.
The semi-solid preparation can be administered, for example by filling a tube with the preparation and sending the preparation directly into the nasal cavity through an applicator attached to the mouth of the tube or by administering the indicated dose of the preparation by means of a nasal insertion device.
While the dosage of the bisphosphonate varies with its kind, the disease to be treated, and the patient to be treated, the proper amount of the solid preparation per dose is about 5 mg to 100 mg, that of the liquid preparation is about 0.05 to 0.5 ml, and that of the semi-solid preparation is about 50 mg to 500 mg. The nasal preparation may be administered from one to about four times per day. The invention also relates to a method for treating patients suffering from a disease where treatment with a bisphosphonate is indicated, such as Paget's disease, hyper- calcaemia due to malignancy, osteoporosis and rheumatoid arthritis, said treatment consisting of administering to the patient in need of treatment an effective amount of the present composition.
The following Examples shall illustrate the invention, but not limit its scope.
Example 1
Nasal absorption of .phenoxymethylene. -bisphosphonic acid (EB 899) in dogs
Preparation I: Disodium (phenoxymethylene)-bisphosphonate: 7.50 g
Water: 60 ml
Ethanol: 10 ml
2N NaOH: 'to pH = 7.6
a
The final solution was diluted with water to a total volume of 100 ml.
Preparation II: Preparation I containing 1 w/v% sodium tauro-24,25- dihydrofusidate (a compound of formula I)
Experiments
Preparation II was sprayed into the nasal cavity of 2 dogs. Preparation I was given either orally, intravenously or nasally (as a spray) to the same two dogs. Urine (0 - 24 hours) was collected in all four experiments and the urinary excretion of EB 899 was determined analytically.
Dog No. Route of ad- Prepara- Dose of Amount % of ministration tion EB 899-di- excreted theory Na (mg) mg
521 nasal II 115.8 51. 3 44 . 3 523 nasal II 123.8 36.2 29 . 3 521 nasal I 120.1 9 . 6 8 . 0 523 nasal I 123.8 10.2 8 .2 521 i.v. I 12.1 7 . 8 64 .5 523 i.v. I 11.7 7 . 1 60.7 521 oral I 130.1 2. 2 1.7
Example 2 The following preparation may be used for the nasal administration of the disodium salt of 3-amino-l-hydroxy- propylidene-1,1-bisphosphonic acid (APD) either as drops or as a spray:
Disodium salt of APD 5.0 g
Sodium tauro-24,25-dihydrofusidate 0.5 g
Water, to a total volume of 100 ml
Example 3 For the nasal administration of 3-(N,N-dimethylamino)- -l-hydroxy-propylidene-l,l-bisphosphonic acid, the following preparation may be used:
Disodium 3-(N,N-dimethylamino)-1-hydroxy-
-propylidene-l,l-bisphosphonate 0.5 g
Water, to total volume of 100 ml
In order to test the nasal absorption of 3-amino-l-hydroxy-propylidene-l,l-bisphosphonic acid, the following preparations were prepared:
Preparation I;
3-Amino-l-hydroxy-propylιdene-
14 -1,1-bisphosphonic acid-1- C 150 mg
Saturated aqueous NaHCO to make a
3 solution with pH = 7.5
Water to make a total volume of 3 ml
Preparation II:
As preparation I but with 15 mg (0.5% w/v) sodium tauro-24,25-dihydrofusidate added.
Three anaesthetized beagle dogs were treated with preparation I either intranasally (as drops) or intra¬ venously. Preparation II was only given intranasally (as drops). Blood samples were drawn at 7, 15, 30, 45 and 60 minutes and at 2, 3, 4, 6 and 24 hours after drug
14 administration. The blood levels of C-APD (pg/ml) were determined by measuring the radioactivity in the blood samples. AϋC (area under blood concentration curve) values were calculated, and the nasal absorption was estimated by comparing AUC-values after nasal and intravenous
administration ,
Dog No. Route of ad- Preparation τζose of AϋC ministration C-APD (h x pg/ml)
219 nasal I 30 mg 2484 413 nasal I 30 mg 2728 514 nasal I 30 mg 2044 103 nasal II 30 mg 2660 213 nasal II 30 mg 3766 229 nasal II 30 mg 2888 103 i.v. I 30 mg 16068 213 i.v. I 30 mg 11992 229 i.v. I 30 mg 15930
Example 5
Nasal absorption of (4-thiomorpholinγlmethylene.bis-
14 phosphonic acid ( C labelled) in dogs
The following preparations were made:
Preparation I
(4-Thiomorpho1inylmethylene)-bisphosphonic acid ( C-labelled) SL 2261- C 150 mg
Saturated aqueous NaHCO to make a solution with pH = 7.5
Water to a total volume of 3 ml
Preparation TT
As preparation I, but with 15 mg (0.5% w/v) sodium tauro-24,25-dihydrofusidate added.
Absorption studies were carried out in 3 beagle dogs as described in Example 4.
Dog Route of Prepara- Dose of AϋC No . admini- tion SL 2261-14C h x pg/ml stration
219 nasal I 30 mg 3280
413 nasal I 30 mg 5306
514 nasal I 30 mg 8398
219 nasal II 30 mg 4686
413 nasal II 30 mg 3058
514 nasal II 30 mg 8288
219 i.v. I 30 mg 8782
413 i.v. I 30 mg 9362
514 i.v. I 30 mg 13518
Claims
1. A composition for the administration of a bis¬ phosphonate to patients in need of treatment, comprising as an active ingredient a bisphosphonate or a salt thereof, together with pharmaceutically acceptable, non-toxic carrier(s) and/or auxiliary agent(s), said compositions being used for nasal administration.
2. A composition according to claim 1, which in addition to the bisphosphonate or a salt thereof contains as an enhancer for the nasal absorption, a compound of the formula I:
in which X (in the α- or β-position) stands for hydrogen, -OH, -O-alkyl, -O-acyl, -S-alkyl, -S-acyl or halogen; Y (in the α- or β-position) stands for -OH, -O-alkyl, -O-acyl, halogen, -O-alkylsulfonyl, or -O-arylsulfonyl; R stands for -OH or -NHZ, Z being alkyl or.aryl, substituted with carboxyl, sulfonic acid groups, and/or quaternary ammonium groups; and in which the dotted lines indicate the possibility of double bond(s);
wherein R , R , and R (in the o- or β-position), which can be the same or different, each stands for hydrogen or -OH, and in which R has the above meanings, provided that not all R , R , and R can be hydrogen at the same time; or a pharmaceutically acceptable salt of such compound of formula I or II.
3. A composition according to claim 1 or 2, in which the bisphosphonate is a member selected from the group consisting of
1-hydroxy-ethylidene-l, 1-b isphosphonic acid; 1-hydroxy-pentylidene-l, 1-b isphosphonic acid; dichloromethylene-b isphosphonic acid; dif luoromethylene-b isphosphonic acid; 3-amino-l-hydroxy-propylidene-l, 1-bisphosphonic acid; 3- (N,N-dimethylamino)-l-hydroxy-propylidene-l, 1-b is¬ phosphonic acid;
3- (N,N-diethylamino) -1-hydroxy-propylidene-l, 1-bisphosphonic acid; 4-amino-l-hydroxy-butylidene-l,l-bisphosphonic acid; 4-(N,N-dimethylamino)-l-hydroxy-butylidene-l,l-bisphosphonic acid; 5-amino-l-hydroxy-pentylidene-l,l-bisphosphonic acid; 6-amino-l-hydroxy-hexylidene-l,l-bisphosphonic acid; , 2- (2 * -pyr idyl) -ethyl idene-1 , 1-b isphosphonic acid; N-(3*-methyl-2'-pyridyl)-aminomethylene-bisphosphonic acid;
(4-chlorophenylthiomethylene)-bisphosphonic acid; (phenoxymethylene)-bisphosphonic acid; (4-thiomorpholinylmethylene)-bisphosphonic acid; (+/-)-(3-isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid;
(+)-(3-isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid;
(-)-(3-isobutyl-4-thiomorpholinylmethylene)-bisphosphonic acid.
4. A composition according to claim 2, in which the enhancer is sodium tauro-24,25-dihydrofusidate (STDF) .
5. A composition according to any one of claims 1-4, in which the bisphosphonate is present in an amount of from 0.005 to 50 (w/v) %, preferably from 0.01 to 30 (w/v) %.
6. A method for the treatment of patients suffering from diseases involving calcium metabolism, such as Paget's disease, hypercalcemia due to malignancy, osteoporosis and rheumatoid arthritis, in which an effective amount of a composition according to any one of claims 1 to 5 is administered to such patients in need of treatment.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK153988A DK153988D0 (en) | 1986-07-25 | 1988-03-22 | PHARMACEUTICAL PREPARATIONS CONTAINING A BISPHOSPHONATE AND THEIR USE FOR NASAL ADMINISTRATION |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB868618259A GB8618259D0 (en) | 1986-07-25 | 1986-07-25 | Pharmaceutical compositions |
GB8618259 | 1986-07-25 |
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Publication Number | Publication Date |
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WO1988000829A1 true WO1988000829A1 (en) | 1988-02-11 |
Family
ID=10601726
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Application Number | Title | Priority Date | Filing Date |
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PCT/DK1987/000084 WO1988000829A1 (en) | 1986-07-25 | 1987-07-03 | Pharmaceutical compositions containing a bisphosphonate and their use for nasal administration |
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Country | Link |
---|---|
EP (1) | EP0276288A1 (en) |
JP (1) | JPH01500754A (en) |
DK (1) | DK153988D0 (en) |
GB (1) | GB8618259D0 (en) |
WO (1) | WO1988000829A1 (en) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0387194A1 (en) * | 1989-03-08 | 1990-09-12 | Ciba-Geigy Ag | N-substituted aminoalkane-diphosphonic acids |
EP0407345A2 (en) * | 1989-07-07 | 1991-01-09 | Ciba-Geigy Ag | Topical formulations |
EP0407344A2 (en) * | 1989-07-07 | 1991-01-09 | Ciba-Geigy Ag | Pharmaceutical preparation for topical application |
US4994439A (en) * | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
US5011678A (en) * | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
US5139786A (en) * | 1989-07-07 | 1992-08-18 | Ciba-Geigy Corporation | Topical formulations |
US5283057A (en) * | 1992-04-24 | 1994-02-01 | The Procter & Gamble Company | Risedronate in oral compositions |
WO1995031203A1 (en) * | 1994-05-17 | 1995-11-23 | Merck & Co., Inc. | Oral liquid alendronate formulations |
WO2000061111A1 (en) * | 1999-04-09 | 2000-10-19 | Astrazeneca Ab | A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate |
WO2000071104A2 (en) * | 1999-05-21 | 2000-11-30 | Novartis Ag | Use of bisphosphonic acids for treating angiogenesis |
US6160165A (en) * | 1998-12-10 | 2000-12-12 | Aesgen, Inc. | Method for preparation of disodium pamidronate |
US6214812B1 (en) * | 1998-04-02 | 2001-04-10 | Mbc Research, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US6406714B1 (en) | 1992-12-02 | 2002-06-18 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids |
EP1310259A2 (en) * | 1997-10-10 | 2003-05-14 | AstraZeneca AB | Formulation comprising a biphosphonate and an absorption enhancing agent for the treatment of osteoporosis |
US6750340B2 (en) | 1998-04-02 | 2004-06-15 | Mbc Research, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US6896871B2 (en) | 1998-04-02 | 2005-05-24 | Mbc Research, Inc. | Biphosphonate conjugates and methods of making and using the same |
US7598246B2 (en) | 1998-04-02 | 2009-10-06 | Mbc Pharma, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US8586781B2 (en) | 1998-04-02 | 2013-11-19 | Mbc Pharma, Inc. | Bone targeted therapeutics and methods of making and using the same |
US9334300B2 (en) | 2011-08-01 | 2016-05-10 | Mbc Pharma, Inc. | Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates |
Citations (7)
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US4067971A (en) * | 1976-05-13 | 1978-01-10 | The Procter & Gamble Company | Therapeutic composition |
US4234645A (en) * | 1977-03-29 | 1980-11-18 | The Procter & Gamble Company | Pharmaceutical composition |
EP0023359A2 (en) * | 1979-07-31 | 1981-02-04 | Teijin Limited | Powdery pharmaceutical composition and powdery preparation for application to the nasal mucosa, and method for administration thereof |
GB2096889A (en) * | 1981-02-12 | 1982-10-27 | Gentili Ist Spa | Pharmaceutical composition containing 6-amino-1-hydroxyhexane-1,1-diphosphonic acid |
EP0128831A2 (en) * | 1983-06-06 | 1984-12-19 | Martin C. Carey | Drug administration |
EP0129285A2 (en) * | 1983-06-21 | 1984-12-27 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl)pyrrolidone |
EP0189662A1 (en) * | 1984-12-21 | 1986-08-06 | The Procter & Gamble Company | Novel diphosphonates and use thereof in pharmaceutical compositions |
-
1986
- 1986-07-25 GB GB868618259A patent/GB8618259D0/en active Pending
-
1987
- 1987-07-03 WO PCT/DK1987/000084 patent/WO1988000829A1/en not_active Application Discontinuation
- 1987-07-03 JP JP62504730A patent/JPH01500754A/en active Pending
- 1987-07-03 EP EP87905191A patent/EP0276288A1/en not_active Withdrawn
-
1988
- 1988-03-22 DK DK153988A patent/DK153988D0/en not_active IP Right Cessation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4067971A (en) * | 1976-05-13 | 1978-01-10 | The Procter & Gamble Company | Therapeutic composition |
US4234645A (en) * | 1977-03-29 | 1980-11-18 | The Procter & Gamble Company | Pharmaceutical composition |
EP0023359A2 (en) * | 1979-07-31 | 1981-02-04 | Teijin Limited | Powdery pharmaceutical composition and powdery preparation for application to the nasal mucosa, and method for administration thereof |
GB2096889A (en) * | 1981-02-12 | 1982-10-27 | Gentili Ist Spa | Pharmaceutical composition containing 6-amino-1-hydroxyhexane-1,1-diphosphonic acid |
EP0128831A2 (en) * | 1983-06-06 | 1984-12-19 | Martin C. Carey | Drug administration |
EP0129285A2 (en) * | 1983-06-21 | 1984-12-27 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl)pyrrolidone |
EP0189662A1 (en) * | 1984-12-21 | 1986-08-06 | The Procter & Gamble Company | Novel diphosphonates and use thereof in pharmaceutical compositions |
Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4994439A (en) * | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
US5011678A (en) * | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
EP0387194A1 (en) * | 1989-03-08 | 1990-09-12 | Ciba-Geigy Ag | N-substituted aminoalkane-diphosphonic acids |
US5036058A (en) * | 1989-03-08 | 1991-07-30 | Ciba-Geigy Corporation | N-substituted aminoalkanediphosphonic acids |
US5133972A (en) * | 1989-07-07 | 1992-07-28 | Ciba-Geigy Corporation | Topically administrable pharmaceutical preparations |
EP0407344A3 (en) * | 1989-07-07 | 1991-06-12 | Ciba-Geigy Ag | Pharmaceutical preparation for topical application |
EP0407345A3 (en) * | 1989-07-07 | 1991-07-24 | Ciba-Geigy Ag | Topical formulations |
EP0407344A2 (en) * | 1989-07-07 | 1991-01-09 | Ciba-Geigy Ag | Pharmaceutical preparation for topical application |
US5139786A (en) * | 1989-07-07 | 1992-08-18 | Ciba-Geigy Corporation | Topical formulations |
AU638034B2 (en) * | 1989-07-07 | 1993-06-17 | Ciba-Geigy Ag | Topical formulations |
EP0407345A2 (en) * | 1989-07-07 | 1991-01-09 | Ciba-Geigy Ag | Topical formulations |
US5283057A (en) * | 1992-04-24 | 1994-02-01 | The Procter & Gamble Company | Risedronate in oral compositions |
US6517867B2 (en) | 1992-12-02 | 2003-02-11 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids |
US6406714B1 (en) | 1992-12-02 | 2002-06-18 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids |
CN1079672C (en) * | 1994-05-17 | 2002-02-27 | 麦克公司 | Oral liquid alendronate formulations |
WO1995031203A1 (en) * | 1994-05-17 | 1995-11-23 | Merck & Co., Inc. | Oral liquid alendronate formulations |
EP1310259A3 (en) * | 1997-10-10 | 2003-05-21 | AstraZeneca AB | Formulation comprising a biphosphonate and an absorption enhancing agent for the treatment of osteoporosis |
EP1310259A2 (en) * | 1997-10-10 | 2003-05-14 | AstraZeneca AB | Formulation comprising a biphosphonate and an absorption enhancing agent for the treatment of osteoporosis |
US6896871B2 (en) | 1998-04-02 | 2005-05-24 | Mbc Research, Inc. | Biphosphonate conjugates and methods of making and using the same |
US8586781B2 (en) | 1998-04-02 | 2013-11-19 | Mbc Pharma, Inc. | Bone targeted therapeutics and methods of making and using the same |
US10046055B2 (en) | 1998-04-02 | 2018-08-14 | Mbc Pharma, Inc. | Bone targeted therapeutics and methods of making and using the same |
US9216204B2 (en) | 1998-04-02 | 2015-12-22 | Mbc Pharma, Inc. | Bone targeted therapeutics and methods of making and using the same |
US6214812B1 (en) * | 1998-04-02 | 2001-04-10 | Mbc Research, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US7598246B2 (en) | 1998-04-02 | 2009-10-06 | Mbc Pharma, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US6750340B2 (en) | 1998-04-02 | 2004-06-15 | Mbc Research, Inc. | Bisphosphonate conjugates and methods of making and using the same |
US6268524B1 (en) | 1998-12-10 | 2001-07-31 | Aesgen, Inc. | Method for preparation of disodium pamidronate |
US6160165A (en) * | 1998-12-10 | 2000-12-12 | Aesgen, Inc. | Method for preparation of disodium pamidronate |
WO2000061111A1 (en) * | 1999-04-09 | 2000-10-19 | Astrazeneca Ab | A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate |
WO2000071104A3 (en) * | 1999-05-21 | 2001-07-19 | Novartis Ag | Use of bisphosphonic acids for treating angiogenesis |
WO2000071104A2 (en) * | 1999-05-21 | 2000-11-30 | Novartis Ag | Use of bisphosphonic acids for treating angiogenesis |
JP2003500352A (en) * | 1999-05-21 | 2003-01-07 | ノバルティス アクチエンゲゼルシャフト | Use of bisphosphonic acid to treat angiogenesis |
US9334300B2 (en) | 2011-08-01 | 2016-05-10 | Mbc Pharma, Inc. | Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates |
Also Published As
Publication number | Publication date |
---|---|
EP0276288A1 (en) | 1988-08-03 |
DK153988A (en) | 1988-03-22 |
DK153988D0 (en) | 1988-03-22 |
JPH01500754A (en) | 1989-03-16 |
GB8618259D0 (en) | 1986-09-03 |
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