CA2205305C - Stable budesonide solutions, method of preparing them and use of these solutions as enema preparations and pharmaceutical foams - Google Patents
Stable budesonide solutions, method of preparing them and use of these solutions as enema preparations and pharmaceutical foams Download PDFInfo
- Publication number
- CA2205305C CA2205305C CA002205305A CA2205305A CA2205305C CA 2205305 C CA2205305 C CA 2205305C CA 002205305 A CA002205305 A CA 002205305A CA 2205305 A CA2205305 A CA 2205305A CA 2205305 C CA2205305 C CA 2205305C
- Authority
- CA
- Canada
- Prior art keywords
- budesonide
- solutions
- solution
- stable
- alcohol
- 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.)
- Expired - Lifetime
Links
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K9/0031—Rectum, anus
Abstract
The present invention relates to stable budeso- nide solutions with a pH of 6.0 or below, which are dissolved in water, alcohol or a water/alcohol mixture. These solutions preferably additionally contain sodium EDTA, cyclodextrin or mixtures thereof. The stable budesonide solutions according to the invention can be used for producing as enema or rectal foams.
Description
Stable budesonide solutions, a process for their preparation, sad the use of these solutions as enema preparations and pharmaceutical foams The present invention relates to stable budeso-nide solutions, the process for their preparation, sad their use for producing pharmaceutical preparations, in particular enemas and pharmaceutical foams.
Budesonide tINN; 16x,17-butylidenedioxy-ll~i.21 dihydroxy-1.4-pregnadiene-3,20-dioae) is a known active substance of the corticoid series which is employed in particular for the treatment of bronchial disorders, but also in cases of inflammatory bowel disorders such as Croha's disease and, in particular, ulcerative colitis. It has proven particularly suitable for the last-mentioned indication to administer rectal drug forms such as enema preparations or pharmaceutical foams in compressed gas packs, because the active substance is employed directly at the site of the disorder, and budesonide is especially topically effective.
Budesonide is a racemate consisting of a mixture of the two diastereomers 22R sad 22S. The racemate can be employed for the purposes of the present invention, but the 22R diastereomer is prefer-ably employed because this is more active in pharmaco-logical respects by a factor of about 2-3. Processes for fractionating the enantiomers are known, for example from W092/11280.
Because of its lipophilicity, budesonide is virtually insoluble in water but is readily soluble in alcohols. An adequate amount of active substance can be dissolved by the use of solubilizers such as organic, water-soluble alcohols. However, the solutions obtained in this way prove to have too little stability for pharmaceutical use because large amounts of the active substance are decomposed within a short time.
_ 2 _ Because of this instability, budesonide preparations which can be used directly by the patient in the administration form ready for use are unknown.
Although budesonide-containing enemas are currently marketed in some countries, in these cases the enemas are not ready for use but comprise a type of combiaa-tioa of tablets containing active substance and enema bottles filled with water. Before administration, the patient must is each case remove a tablet, introduce it into the opened enema bottle, wait until the tablet has disintegrated and shake the bottles vigorously before use is order to disperse the active substance as homo-geneously as possible in the form of a suspension.
This. laborious and troublesome preparation of the enema ready for use can be only inadequately accom plished is particular by frail patients. Homogeneous dispersion of the active substance can be achieved only inadequately by this process, and complete administra tion of the active substance by squeezing of the enema bottle can scarcely be guaranteed because there is a tendency for the suspended active substance to settle out on the bottom of the bottle is a short time after preparation of the final form.
Although rectal administration of budesonide by means of rectal foams has advantages in respect of convenience of uae, the problem here is to provide budesonide solutions which have adequate stability for administration in compressed gas packs. Budesonide containiag rectal foams have therefore not hitherto been disclosed.
One object of the present invention is to provide adequately stable solutions of budesonide.
This object is achieved by budesonide solutions which have a pH of 6 or below.
It has been found, completely surprisingly, that the stability of budesonide-containing solutions depends crucially on the pH. The stability of the solutions increases as the pH decreases. The budesonide solutions according to the invention can be prepared on an aqueous -and/or alcoholic basis, it also being possible to dissolve budesonide in as aqueous, alcoholic mixture.
It has been found, completely surprisingly, is the framework of the present invention that the pH has a crucial influence on the stability of the budesonide solution, specifically in aqueous, aqueous-alcoholic or alcoholic solution.
Table 1 which is shown hereinafter proves the stability of an aqueous solution of budesonide and Table 2 shows the stability of an alcoholic solution (propylene glycol) of budesonide as a function of the storage time and the pH.
Table 1 Stability of budesonide solutions according to the invention (2 mg/60 ml of H20) as a function of the storage time Contentsi~ storage for 14 after days at pH 20C 40C
7.0 96.5 % 71.2 %
6.5 96.4 % 77.1 %
6.0 97.6 % 84.8 %
5.5 97.4 % 87.6 %
5.0 97.6 % 90.0 %
4.5 97.3 % 93.0 %
4.0 98.7 % 95.2 %
3.5 99.8 % 96.6 %
3.0 100.0 % 97.9 %
1' Initial value after t = 0 days equal to 100 %
It is evident from Table 1 above that the stability of the solutions increases as the pH
decreases. Even after storage at 20°C and pH 3.0 for 14 days, the active substance is still 100 % present.
Even on storage at a distinctly ha.gher temperature, that is to say at 40°C and pH 3.0, there is still 97.9 % budesonide is the solution after 14 days.
Table 2 Stability of budesonide solutions according to the invention (2 mg/4 g in propylene glycol) as a function of the storage time Content after storage at pH 0 months 3 months 3 months 6 months 7.5 100.0 % 80.6 % 44.4 % 15.3 %
5.0 100.0 % 103.0 % 96.5 % 89.5 %
Budesonide tINN; 16x,17-butylidenedioxy-ll~i.21 dihydroxy-1.4-pregnadiene-3,20-dioae) is a known active substance of the corticoid series which is employed in particular for the treatment of bronchial disorders, but also in cases of inflammatory bowel disorders such as Croha's disease and, in particular, ulcerative colitis. It has proven particularly suitable for the last-mentioned indication to administer rectal drug forms such as enema preparations or pharmaceutical foams in compressed gas packs, because the active substance is employed directly at the site of the disorder, and budesonide is especially topically effective.
Budesonide is a racemate consisting of a mixture of the two diastereomers 22R sad 22S. The racemate can be employed for the purposes of the present invention, but the 22R diastereomer is prefer-ably employed because this is more active in pharmaco-logical respects by a factor of about 2-3. Processes for fractionating the enantiomers are known, for example from W092/11280.
Because of its lipophilicity, budesonide is virtually insoluble in water but is readily soluble in alcohols. An adequate amount of active substance can be dissolved by the use of solubilizers such as organic, water-soluble alcohols. However, the solutions obtained in this way prove to have too little stability for pharmaceutical use because large amounts of the active substance are decomposed within a short time.
_ 2 _ Because of this instability, budesonide preparations which can be used directly by the patient in the administration form ready for use are unknown.
Although budesonide-containing enemas are currently marketed in some countries, in these cases the enemas are not ready for use but comprise a type of combiaa-tioa of tablets containing active substance and enema bottles filled with water. Before administration, the patient must is each case remove a tablet, introduce it into the opened enema bottle, wait until the tablet has disintegrated and shake the bottles vigorously before use is order to disperse the active substance as homo-geneously as possible in the form of a suspension.
This. laborious and troublesome preparation of the enema ready for use can be only inadequately accom plished is particular by frail patients. Homogeneous dispersion of the active substance can be achieved only inadequately by this process, and complete administra tion of the active substance by squeezing of the enema bottle can scarcely be guaranteed because there is a tendency for the suspended active substance to settle out on the bottom of the bottle is a short time after preparation of the final form.
Although rectal administration of budesonide by means of rectal foams has advantages in respect of convenience of uae, the problem here is to provide budesonide solutions which have adequate stability for administration in compressed gas packs. Budesonide containiag rectal foams have therefore not hitherto been disclosed.
One object of the present invention is to provide adequately stable solutions of budesonide.
This object is achieved by budesonide solutions which have a pH of 6 or below.
It has been found, completely surprisingly, that the stability of budesonide-containing solutions depends crucially on the pH. The stability of the solutions increases as the pH decreases. The budesonide solutions according to the invention can be prepared on an aqueous -and/or alcoholic basis, it also being possible to dissolve budesonide in as aqueous, alcoholic mixture.
It has been found, completely surprisingly, is the framework of the present invention that the pH has a crucial influence on the stability of the budesonide solution, specifically in aqueous, aqueous-alcoholic or alcoholic solution.
Table 1 which is shown hereinafter proves the stability of an aqueous solution of budesonide and Table 2 shows the stability of an alcoholic solution (propylene glycol) of budesonide as a function of the storage time and the pH.
Table 1 Stability of budesonide solutions according to the invention (2 mg/60 ml of H20) as a function of the storage time Contentsi~ storage for 14 after days at pH 20C 40C
7.0 96.5 % 71.2 %
6.5 96.4 % 77.1 %
6.0 97.6 % 84.8 %
5.5 97.4 % 87.6 %
5.0 97.6 % 90.0 %
4.5 97.3 % 93.0 %
4.0 98.7 % 95.2 %
3.5 99.8 % 96.6 %
3.0 100.0 % 97.9 %
1' Initial value after t = 0 days equal to 100 %
It is evident from Table 1 above that the stability of the solutions increases as the pH
decreases. Even after storage at 20°C and pH 3.0 for 14 days, the active substance is still 100 % present.
Even on storage at a distinctly ha.gher temperature, that is to say at 40°C and pH 3.0, there is still 97.9 % budesonide is the solution after 14 days.
Table 2 Stability of budesonide solutions according to the invention (2 mg/4 g in propylene glycol) as a function of the storage time Content after storage at pH 0 months 3 months 3 months 6 months 7.5 100.0 % 80.6 % 44.4 % 15.3 %
5.0 100.0 % 103.0 % 96.5 % 89.5 %
2.8 100.0 % 99.4 % 98.7 % 95.2 %
It is evident from Table 2 above that the stability of the solutions increases as the pH
decreases.
The losses of active substance at pH values of 4.0 and below are sufficiently low to be of an accept able magnitude as a function of the storage time for pharmaceutical products.
For pharmaceutical use, the preferred pH values of the form ready for use are >_ 3.5 for use as enema or else as rectal foam because of the physiological factors and taking account of the amount of about 30 to 100 ml to be administered for enemas and, of about 4 g in the case of rectal foams.
Any pharmaceutically acceptable organic and inorganic acids can be used to adjust the pH, for example hydrochloric acid, phosphoric acid, citric acid or tartaric acid.
Ia order to increase the stability further, for example to save transport and storage costs, or else for use as non-rectal administration form, it is also possible to prepare concentrated budesoaide solutions with a pH <_ 3.5. If it is necessary for subsequent use to adjust the pH to a physiologically tolerated value > 3.5, this can take place only shortly before use.
This can happen, for example. by dilution or by addition of a base. The dilution process then increases the pH.
In other preferred embodiments, the budesonide solutions according to the invention have an addition of sodium EDTA (sodium ethylenediamiaetetraacetic acid:
KomplexonTM), which further increases the stability.
Ia another preferred embodiment of the present invention, the stability of the solution can be increased by. using cyclodextrins, preferably hydroxy-propyl-(3-cyclodextrin or Y-cyclodextria. Addition of cyclodextrins also makes it possible to use more concentrated solutions of budesonide.
The invention therefore relates to stable budesonide solutions with a pH of 6'.0 or below. The budesonide is dissolved according to the invention in water, alcohol or a water/alcohol mixture.
The alcohols used for the purposes of the present invention are preferably propylene glycol, ethanol or isopropanol.
When an alcohol/water mixture is employed, the ratio of alcohol to water is between 100:0 and 80:20, preferably between 98:2 and 93:7.
The budesonide content in the solution ready for use is between 0.001 and 1 % by weight, preferably between 0.01 and 0.1 % by weight and, is the case of enemas, is particularly preferably 0.001 to 0.1 % by weight.
The solutions according to the invention may furthermore contain ancillary substances customarily used in corresponding pharmaceutical formulations.
These ancillary substances may be suitable for solubi-lizing corticoids. The skilled worker is familiar with ancillary substances of this type.
Conventional ancillary substances are those which influence, normally increase, the viscosity of the solution, preservatives such as ethanol, chloro-butanol, benzyl alcohol, phenylethanol, sorbic acid, benzoic acid, sodium diaulfite, p-hydroxybeazoates, phenol, m-cresol, p-chloro-m-cresol, goats, chloro-hexidine, thickeners such as gelatin, tragacanth, pectin, cellulose derivatives (for example methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium), polyvinylpyrrolidoae, polyvinyl alcohol, polyacrylic acids, xaathan gum, acids such as acetic acid, citric acid, tartaric acid, hydrochloric acid, phosphoric acid; bases such as potassium hydroxide, sodium hydroxide; buffer substances such as hydrochloric acid buffer, phthalate 15, buffer, phosphate buffer, borate buffer, acetate buffer or citrate buffer. In order to increase the solubility of the active substance, it is suitable, for example, to add sufficient amounts of alcohols such as ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycols or to use solubilizers such as, for example, cyclodextrias, preferably [3-cyclodextrin, hydroxypropyl-(3-cyclodextria and/or y-cyclodextrin.
If the budesonide solutions according to the invention are intended for use as rectal foams, it i.s necessary to add those customary ancillary substances which first make it possible for the dispersion to form. Ancillary substances of this type are emulsifiers known to the skilled worker, such as Eumulgins and various Lunette types. It is furthermore possible to add preservatives such as sorbic acid, parahydroxy-benzoates, benzoic acid, acids such as acetic acid, citric acid, tartaric acid, hydrochloric acid and phosphoric acid.
In the case of rectal foams, suitable propellant gases are also introduced into the pressure packs. Even if chlorofluorocarbon gases were suitable as propellant gases, the use of these gases tends to be avoided at present for reasons of environmental protection. The propellant gases preferably used are therefore hydrocarbons such as isobutane, n-butane or propane/n-butane mixtures.
The pH of the budesonide solutions according to the invention is 6.0 or below. A range between 5.0 and 3.5 is preferred, and the pH range between 4.5 and 4.0 is particularly preferred.
Budesoaide is present in the solutions according to the invention in an amount between 0.001 and 1 ~ by weight, with the concentration in solutions intended to be used as enemas being lower than in solutions intended for rectal foams. The preferred concentration in solutions for enemas is between 0.01 and 0.1 ~ by weight, and the preferred range for rectal foams is between 0.01 and 0.1 ~ by weight.
Sodium EDTA is preferably added in an amount of 0.01 to 1.0 ~ by weight, with a range from 0.01 to 0.1 ~ by weight being preferred for enemas and a concentration of 0.05 to 1 ~ by weight being preferred for rectal foams.
Whereas cyclodextrins are added as solubi-lizers, this preferably takes place is an amount between 0.05 and 0.5 ~ by weight, with addition of about 0.1 ~ by weight being preferred.
Solutions for enemas are prepared by processes known per se. It is possible, for example, to incorporate an ethanolic stock solution of budesonide into as aqueous solution of the other ingredients with homogenization. The use of an antioxidant or exclusion of oxygen, and measures .ia the area of protection from light are not specifically necessary but they may improve the quality and the stability of the resulting products. For rectal use, the finished solution is then dispensed into a conventional flexible enema bottle with applicator tip, both of which are preferably produced from opaque plastic.
The preparation of solutions for rectal foams is also known in the prior art. For example, the preservative and the emulsifiers required for foam formation can be dissolved i.n the appropriate solution, preferably the suitable alcohol. The active substance is then incorporated as alcoholic stock solution into this solution. In the last step, Komplexoa and the appropriate acid, dissolved is a small amount of water, are stirred into the alcoholic solution with homogeni-zation.
If the budesonide solution according to the invention is used to produce a rectal foam, the finished solution is introduced into suitable compressed gas packs which are provided with commer-cially obtainable valve systems as single or multiple dose~devices, and a propellant gas is added. The packs additionally contain an applicator tip made of plastic.
Because of the chemical and physical properties of the stable budesonide solution according to the invention, the foam is inevitably generated in the rectum on administration.
In a preferred embodiment, the stable budeso nide solutions according to the invention are used to produce enemas or rectal' foams. Other use forms such as, for example, use as metered aerosol, inhalation spray or else as drops, syrup or elixirs are likewise possible and can easily be produced by the skilled worker oa the basis of the present description. The invention is explained in detail by means of the following examples.
8xamnle 1 A solution is prepared by the process described above and is dispensed into appropriate plastic bottles and contains the following ingredients per 60 g enema bottle:
budesonide 2 mg ~i-cyclodextria, hydroxypropyl-~-cyclo-dextrin (0.9) or y-cyclodextria 60 mg sodium EDTA 30 mg sodium benzoate 300 mg xanthaa gum 360 mg _ g _ 2N HCl ad pH 4.0 ethanol 400 mg water ad 60.00 mg The solution produced is this way proved to be stable even after storage at 40°C for several weeks.
Example 2 Enema produced by the customary process, containing budesoaide 2 mg sodium benzoate 300 mg sodium EDTA 30 mg propylene glycol 500 mg xanthaa gum 360 mg 2N hydrochloric acid ad pH 3.5 60.00 mg The enema produced is this way proved to be stable after storage at 40°C for several weeks.
Example 3 An aqueous solution is produced as in Example 1 and contains the following ingredients:
budesoaide 2 mg (3-cyclodextrin, hydroxypropyl-(3-cyclo-dextria (0.9) or y-cyclodextrin 60 mg sodium benzoate 300 mg xanthan gum 360 mg 2N HC1 ad pH 4.0 ethanol 400 mg water ad 60.00 mg The solution produced in this way proved to be stable even after storage at room temperature for several weeks.
Example 4 Aa aqueous solution is produced as in Example 1 and contains the following ingredients:
- to -budesonide 2 mg sodium EDTA 30 mg sodium benzoate 300 mg xanthan gum 360 mg 2N HC1 ad pH 4.0 ethanol 400 mg water ad ' 60.00 mg The solution produced in this way proved to be stable even after storage at room temperature for several weeks.
Exaamle 5 An aqueous solution is produced as in Example 1 and contains the following ingredients:
budesoaide 2 mg sodium benzoate 300 mg xanthan gum 360 mg 2N HC1 ad pH 4.0 ethanol 400 mg water ad 60.00 mg The solution produced i.n this way proved to be stable even after storage at room temperature for several weeks.
Example 6 Investigation of the stability of the solutions according to the invention The formulations in the following Table 3 were produced as in Example 1 and investigated for their stability after storage for 1 to 39 weeks. The follow-ing results were obtained.
Table 3 Contents Stress time in ... at 40C
weeks pH 5, without 96.1 % 67.6 % 60.2 %56.6 %
additions pH 4, with BDTA, with 100.0 %99.6 99.8 % 97.3 % %
y-cyclodextrin pH 4, with 100.0 %94.7 95.0 % 89.4 % %
SDTA, with hydroxypropyl-(3-cyclodextrin (molar degree of substitution 0.9) pH 4, with 98.8 % 93.1 %
EDTA, with propylene glycol i Initial value at t = 0 weeks = 100 %
The above test results prove that the aqueous budesonide solutions according to the invention with a pH below 6 are still stable even after storage for several weeks. Solutions which contain EDTA and a cyclodextrin are particularly stable. Thus, these solutions still contain 100 ~ of active substance even after storage at 40°C and pH 4 for six weeks.
Example 7 A solution is prepared by the process described above and i.s dispensed into appropriate compressed gas packs (for example aluminum monoblock can, 55 ml, with liquid valve, shield and metering head) with the addition of a propellant gas (pressure > 1.5 bar, such as, for example, isobutane, n-butane, propane/n-butane mixtures).
The solution contains the following ingredients J
per 35 g:
budesonide 0.01820 g Laaette 0 0.45500 g Eumulgin B1 0.09100 g Eumulgia B2 0.09100 g sorbic acid 0.00845 g Romplexon ~ 0.03000 g citric acid ad pH 3.5 0.01000 g aqua purificata 0.90000 g propylene glycol ad 35.0000 g The solution produced is this way proved to be stable after storage at 40°C for several moaths.
Example 8 budesonide 0.01820 g Lanette 0 0.45500 g Eumulgin B1 0.09100 g Eumulgin B2 0.09100 g benzoic acid 0.06000 g citric acid ad pH 4.0 q.s.
aqua purificata 0.90000 g propylene glycol ad 35.0000 g The solutioa produced in this way proved to be stable after storage at 40°C for several months.
Example 9 budesonide 0.01820 g Lanette 0 0.45500 g Eumulgia Bl 0.09100 g Eumulgin B2 0.09100 g Romplexon 0.03000 g tartaric acid ad pH 4.5 q.s.
aqua purificata 0.90000 g propylene glycol ad 35.0000 g The solution produced is this way proved to be stable after storage at 40°C for several months.
Example 10 Investigations of the stability of the solutions according to the invention Formulations were produced as in Example 7 with different pH values and were investigated for their stability after storage for 0 - 6 months. The following results were optained:
Content after storage at pH 0 months 3 months 3 months 6 months 7.5 without 100.0 % 90.4 % 75.0 % not additions determined 7.5 With 100.0 % 103.0 % 96.5 % 89.5 %
Romplexon 4.5 100.0 % 102.5 % 97.8 % 94.6 %
(94073) (9 months) with Rom-lexon, with citric acid 4.0 100.0 % 97.6 % 98.0 % -(95030) with Rom-lexon, with citric acid 3.5 100.0 % 100.8- % 100.2 % - -(95035) with Rom-lexon, With citric acid Table 4 The above test results prove that the alcoholic budesonide solutions according to the invention with a pH below 6 are still stable even after storage for several months. Solutions, which additionally contain FComplexoa are particularly stable. The losses of active substance occurring even after storage at 40°C for 6 -9 months are extremely small.
It is evident from Table 2 above that the stability of the solutions increases as the pH
decreases.
The losses of active substance at pH values of 4.0 and below are sufficiently low to be of an accept able magnitude as a function of the storage time for pharmaceutical products.
For pharmaceutical use, the preferred pH values of the form ready for use are >_ 3.5 for use as enema or else as rectal foam because of the physiological factors and taking account of the amount of about 30 to 100 ml to be administered for enemas and, of about 4 g in the case of rectal foams.
Any pharmaceutically acceptable organic and inorganic acids can be used to adjust the pH, for example hydrochloric acid, phosphoric acid, citric acid or tartaric acid.
Ia order to increase the stability further, for example to save transport and storage costs, or else for use as non-rectal administration form, it is also possible to prepare concentrated budesoaide solutions with a pH <_ 3.5. If it is necessary for subsequent use to adjust the pH to a physiologically tolerated value > 3.5, this can take place only shortly before use.
This can happen, for example. by dilution or by addition of a base. The dilution process then increases the pH.
In other preferred embodiments, the budesonide solutions according to the invention have an addition of sodium EDTA (sodium ethylenediamiaetetraacetic acid:
KomplexonTM), which further increases the stability.
Ia another preferred embodiment of the present invention, the stability of the solution can be increased by. using cyclodextrins, preferably hydroxy-propyl-(3-cyclodextrin or Y-cyclodextria. Addition of cyclodextrins also makes it possible to use more concentrated solutions of budesonide.
The invention therefore relates to stable budesonide solutions with a pH of 6'.0 or below. The budesonide is dissolved according to the invention in water, alcohol or a water/alcohol mixture.
The alcohols used for the purposes of the present invention are preferably propylene glycol, ethanol or isopropanol.
When an alcohol/water mixture is employed, the ratio of alcohol to water is between 100:0 and 80:20, preferably between 98:2 and 93:7.
The budesonide content in the solution ready for use is between 0.001 and 1 % by weight, preferably between 0.01 and 0.1 % by weight and, is the case of enemas, is particularly preferably 0.001 to 0.1 % by weight.
The solutions according to the invention may furthermore contain ancillary substances customarily used in corresponding pharmaceutical formulations.
These ancillary substances may be suitable for solubi-lizing corticoids. The skilled worker is familiar with ancillary substances of this type.
Conventional ancillary substances are those which influence, normally increase, the viscosity of the solution, preservatives such as ethanol, chloro-butanol, benzyl alcohol, phenylethanol, sorbic acid, benzoic acid, sodium diaulfite, p-hydroxybeazoates, phenol, m-cresol, p-chloro-m-cresol, goats, chloro-hexidine, thickeners such as gelatin, tragacanth, pectin, cellulose derivatives (for example methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium), polyvinylpyrrolidoae, polyvinyl alcohol, polyacrylic acids, xaathan gum, acids such as acetic acid, citric acid, tartaric acid, hydrochloric acid, phosphoric acid; bases such as potassium hydroxide, sodium hydroxide; buffer substances such as hydrochloric acid buffer, phthalate 15, buffer, phosphate buffer, borate buffer, acetate buffer or citrate buffer. In order to increase the solubility of the active substance, it is suitable, for example, to add sufficient amounts of alcohols such as ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycols or to use solubilizers such as, for example, cyclodextrias, preferably [3-cyclodextrin, hydroxypropyl-(3-cyclodextria and/or y-cyclodextrin.
If the budesonide solutions according to the invention are intended for use as rectal foams, it i.s necessary to add those customary ancillary substances which first make it possible for the dispersion to form. Ancillary substances of this type are emulsifiers known to the skilled worker, such as Eumulgins and various Lunette types. It is furthermore possible to add preservatives such as sorbic acid, parahydroxy-benzoates, benzoic acid, acids such as acetic acid, citric acid, tartaric acid, hydrochloric acid and phosphoric acid.
In the case of rectal foams, suitable propellant gases are also introduced into the pressure packs. Even if chlorofluorocarbon gases were suitable as propellant gases, the use of these gases tends to be avoided at present for reasons of environmental protection. The propellant gases preferably used are therefore hydrocarbons such as isobutane, n-butane or propane/n-butane mixtures.
The pH of the budesonide solutions according to the invention is 6.0 or below. A range between 5.0 and 3.5 is preferred, and the pH range between 4.5 and 4.0 is particularly preferred.
Budesoaide is present in the solutions according to the invention in an amount between 0.001 and 1 ~ by weight, with the concentration in solutions intended to be used as enemas being lower than in solutions intended for rectal foams. The preferred concentration in solutions for enemas is between 0.01 and 0.1 ~ by weight, and the preferred range for rectal foams is between 0.01 and 0.1 ~ by weight.
Sodium EDTA is preferably added in an amount of 0.01 to 1.0 ~ by weight, with a range from 0.01 to 0.1 ~ by weight being preferred for enemas and a concentration of 0.05 to 1 ~ by weight being preferred for rectal foams.
Whereas cyclodextrins are added as solubi-lizers, this preferably takes place is an amount between 0.05 and 0.5 ~ by weight, with addition of about 0.1 ~ by weight being preferred.
Solutions for enemas are prepared by processes known per se. It is possible, for example, to incorporate an ethanolic stock solution of budesonide into as aqueous solution of the other ingredients with homogenization. The use of an antioxidant or exclusion of oxygen, and measures .ia the area of protection from light are not specifically necessary but they may improve the quality and the stability of the resulting products. For rectal use, the finished solution is then dispensed into a conventional flexible enema bottle with applicator tip, both of which are preferably produced from opaque plastic.
The preparation of solutions for rectal foams is also known in the prior art. For example, the preservative and the emulsifiers required for foam formation can be dissolved i.n the appropriate solution, preferably the suitable alcohol. The active substance is then incorporated as alcoholic stock solution into this solution. In the last step, Komplexoa and the appropriate acid, dissolved is a small amount of water, are stirred into the alcoholic solution with homogeni-zation.
If the budesonide solution according to the invention is used to produce a rectal foam, the finished solution is introduced into suitable compressed gas packs which are provided with commer-cially obtainable valve systems as single or multiple dose~devices, and a propellant gas is added. The packs additionally contain an applicator tip made of plastic.
Because of the chemical and physical properties of the stable budesonide solution according to the invention, the foam is inevitably generated in the rectum on administration.
In a preferred embodiment, the stable budeso nide solutions according to the invention are used to produce enemas or rectal' foams. Other use forms such as, for example, use as metered aerosol, inhalation spray or else as drops, syrup or elixirs are likewise possible and can easily be produced by the skilled worker oa the basis of the present description. The invention is explained in detail by means of the following examples.
8xamnle 1 A solution is prepared by the process described above and is dispensed into appropriate plastic bottles and contains the following ingredients per 60 g enema bottle:
budesonide 2 mg ~i-cyclodextria, hydroxypropyl-~-cyclo-dextrin (0.9) or y-cyclodextria 60 mg sodium EDTA 30 mg sodium benzoate 300 mg xanthaa gum 360 mg _ g _ 2N HCl ad pH 4.0 ethanol 400 mg water ad 60.00 mg The solution produced is this way proved to be stable even after storage at 40°C for several weeks.
Example 2 Enema produced by the customary process, containing budesoaide 2 mg sodium benzoate 300 mg sodium EDTA 30 mg propylene glycol 500 mg xanthaa gum 360 mg 2N hydrochloric acid ad pH 3.5 60.00 mg The enema produced is this way proved to be stable after storage at 40°C for several weeks.
Example 3 An aqueous solution is produced as in Example 1 and contains the following ingredients:
budesoaide 2 mg (3-cyclodextrin, hydroxypropyl-(3-cyclo-dextria (0.9) or y-cyclodextrin 60 mg sodium benzoate 300 mg xanthan gum 360 mg 2N HC1 ad pH 4.0 ethanol 400 mg water ad 60.00 mg The solution produced in this way proved to be stable even after storage at room temperature for several weeks.
Example 4 Aa aqueous solution is produced as in Example 1 and contains the following ingredients:
- to -budesonide 2 mg sodium EDTA 30 mg sodium benzoate 300 mg xanthan gum 360 mg 2N HC1 ad pH 4.0 ethanol 400 mg water ad ' 60.00 mg The solution produced in this way proved to be stable even after storage at room temperature for several weeks.
Exaamle 5 An aqueous solution is produced as in Example 1 and contains the following ingredients:
budesoaide 2 mg sodium benzoate 300 mg xanthan gum 360 mg 2N HC1 ad pH 4.0 ethanol 400 mg water ad 60.00 mg The solution produced i.n this way proved to be stable even after storage at room temperature for several weeks.
Example 6 Investigation of the stability of the solutions according to the invention The formulations in the following Table 3 were produced as in Example 1 and investigated for their stability after storage for 1 to 39 weeks. The follow-ing results were obtained.
Table 3 Contents Stress time in ... at 40C
weeks pH 5, without 96.1 % 67.6 % 60.2 %56.6 %
additions pH 4, with BDTA, with 100.0 %99.6 99.8 % 97.3 % %
y-cyclodextrin pH 4, with 100.0 %94.7 95.0 % 89.4 % %
SDTA, with hydroxypropyl-(3-cyclodextrin (molar degree of substitution 0.9) pH 4, with 98.8 % 93.1 %
EDTA, with propylene glycol i Initial value at t = 0 weeks = 100 %
The above test results prove that the aqueous budesonide solutions according to the invention with a pH below 6 are still stable even after storage for several weeks. Solutions which contain EDTA and a cyclodextrin are particularly stable. Thus, these solutions still contain 100 ~ of active substance even after storage at 40°C and pH 4 for six weeks.
Example 7 A solution is prepared by the process described above and i.s dispensed into appropriate compressed gas packs (for example aluminum monoblock can, 55 ml, with liquid valve, shield and metering head) with the addition of a propellant gas (pressure > 1.5 bar, such as, for example, isobutane, n-butane, propane/n-butane mixtures).
The solution contains the following ingredients J
per 35 g:
budesonide 0.01820 g Laaette 0 0.45500 g Eumulgin B1 0.09100 g Eumulgia B2 0.09100 g sorbic acid 0.00845 g Romplexon ~ 0.03000 g citric acid ad pH 3.5 0.01000 g aqua purificata 0.90000 g propylene glycol ad 35.0000 g The solution produced is this way proved to be stable after storage at 40°C for several moaths.
Example 8 budesonide 0.01820 g Lanette 0 0.45500 g Eumulgin B1 0.09100 g Eumulgin B2 0.09100 g benzoic acid 0.06000 g citric acid ad pH 4.0 q.s.
aqua purificata 0.90000 g propylene glycol ad 35.0000 g The solutioa produced in this way proved to be stable after storage at 40°C for several months.
Example 9 budesonide 0.01820 g Lanette 0 0.45500 g Eumulgia Bl 0.09100 g Eumulgin B2 0.09100 g Romplexon 0.03000 g tartaric acid ad pH 4.5 q.s.
aqua purificata 0.90000 g propylene glycol ad 35.0000 g The solution produced is this way proved to be stable after storage at 40°C for several months.
Example 10 Investigations of the stability of the solutions according to the invention Formulations were produced as in Example 7 with different pH values and were investigated for their stability after storage for 0 - 6 months. The following results were optained:
Content after storage at pH 0 months 3 months 3 months 6 months 7.5 without 100.0 % 90.4 % 75.0 % not additions determined 7.5 With 100.0 % 103.0 % 96.5 % 89.5 %
Romplexon 4.5 100.0 % 102.5 % 97.8 % 94.6 %
(94073) (9 months) with Rom-lexon, with citric acid 4.0 100.0 % 97.6 % 98.0 % -(95030) with Rom-lexon, with citric acid 3.5 100.0 % 100.8- % 100.2 % - -(95035) with Rom-lexon, With citric acid Table 4 The above test results prove that the alcoholic budesonide solutions according to the invention with a pH below 6 are still stable even after storage for several months. Solutions, which additionally contain FComplexoa are particularly stable. The losses of active substance occurring even after storage at 40°C for 6 -9 months are extremely small.
Claims (9)
1. A stable sodium-EDTA containing budesonide-solution with a pH between 5.0 and 3.5, wherein the budesonide is dissolved in a solvent selected from the group consisting of water, alcohol or a water/alcohol-mixture, wherein the alcohol is selected from the group consisting of ethanol, isopropanol or propylene glycol and which contains 0.01 to 0.1 % by weight of sodium EDTA.
2. A stable budesonide-solution as claimed in claim 1 which additionally comprises cyclodextrin.
3. A stable budesonide-solution as claimed in any of 1 or 2 claims which comprises 0.001 to 0.1 % by weight of budesonide.
4. A stable budesonide-solution as claimed in any of claims 1 to 3 which comprises 0.05 to 1.0 % by weight of cyclodextrins.
5. A process for producing stable budesonid containing solutions as claimed in any of claims 1 to 4 which comprises dissolving of budesonid and sodium-EDTA in a solvent selected from the group consisting of water, alcohol or a water/alcohol-mixture whereby the alcohol is selected from the group consisting of ethanol, isopropanol or propylene glycol and adjusting the pH of the budesonide solution between 5.0 to 3.5.
6. An enema which comprises a stable budesonide-solution as claimed in any of claims 1 to 4.
7. A rectal foam which comprises a stable aqueous budesonide-solution as claimed in any of claims 1 to 4.
8. The use of a stable budesonide-solution as claimed in any of claims 1 to 4 for producing an enema.
9. The use of a stable budesonide-solution as claimed in any of claims 1 to 4 for producing a rectal foam.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4446891.1 | 1994-12-27 | ||
| DE4446891A DE4446891A1 (en) | 1994-12-27 | 1994-12-27 | Stable aqueous budesonide solution |
| PCT/DE1995/001847 WO1996019969A1 (en) | 1994-12-27 | 1995-12-19 | Stable budesonide solutions, method of preparing them and use of these solutions as enema preparations and pharmaceutical foams |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2205305A1 CA2205305A1 (en) | 1996-07-04 |
| CA2205305C true CA2205305C (en) | 2002-05-07 |
Family
ID=6537317
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002205305A Expired - Lifetime CA2205305C (en) | 1994-12-27 | 1995-12-19 | Stable budesonide solutions, method of preparing them and use of these solutions as enema preparations and pharmaceutical foams |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5914122A (en) |
| EP (1) | EP0794767B1 (en) |
| JP (1) | JP3421348B2 (en) |
| AT (1) | ATE168556T1 (en) |
| CA (1) | CA2205305C (en) |
| DE (2) | DE4446891A1 (en) |
| DK (1) | DK0794767T3 (en) |
| ES (1) | ES2120247T3 (en) |
| GR (1) | GR3027632T3 (en) |
| WO (1) | WO1996019969A1 (en) |
Families Citing this family (110)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4990696A (en) * | 1995-02-24 | 1996-09-11 | Nanosystems L.L.C. | Aerosols containing nanoparticle dispersions |
| GB9504265D0 (en) * | 1995-03-03 | 1995-04-19 | Medeva Plc | Corticosteroid-containing pharmaceutical composition |
| CN1086575C (en) | 1995-06-27 | 2002-06-26 | 贝林格尔·英格海姆公司 | New stable medicinal compositions for generating propellant-free aerosols |
| US5863910A (en) * | 1996-01-12 | 1999-01-26 | Bolonick; Joel | Treatment of chronic inflammatory disorders of the gastrointestinal tract |
| US20010031244A1 (en) | 1997-06-13 | 2001-10-18 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
| US6598603B1 (en) * | 1997-12-31 | 2003-07-29 | Astra Aktiebolag | Method for treating respiratory diseases |
| ES2201673T3 (en) * | 1998-02-11 | 2004-03-16 | Rtp Pharma Corporation | COMBINATION OF STEROIDS AND POIINSATURED FATTY ACIDS FOR THE TREATMENT OF INFLAMMATORY STATES. |
| US6451285B2 (en) * | 1998-06-19 | 2002-09-17 | Baker Norton Pharmaceuticals, Inc. | Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant |
| US6234167B1 (en) | 1998-10-14 | 2001-05-22 | Chrysalis Technologies, Incorporated | Aerosol generator and methods of making and using an aerosol generator |
| US20090297602A1 (en) * | 1998-11-02 | 2009-12-03 | Devane John G | Modified Release Loxoprofen Compositions |
| US6344218B1 (en) | 1998-11-23 | 2002-02-05 | The Procter & Gamble Company | Skin deodorizing and santizing compositions |
| DZ2947A1 (en) | 1998-11-25 | 2004-03-15 | Chiesi Farma Spa | Pressure metered dose inhaler. |
| US7074388B2 (en) * | 1998-12-10 | 2006-07-11 | Kos Life Science, Inc. | Water stabilized medicinal aerosol formulation |
| US20060171899A1 (en) * | 1998-12-10 | 2006-08-03 | Akwete Adjei | Water-stabilized aerosol formulation system and method of making |
| US6290930B1 (en) * | 1998-12-18 | 2001-09-18 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes and budesonide |
| IT1313553B1 (en) | 1999-07-23 | 2002-09-09 | Chiesi Farma Spa | OPTIMIZED FORMULATIONS CONSTITUTED BY SOLUTIONS OF STEROIDS GIVEN BY INHALATION. |
| US6479035B1 (en) * | 1999-09-11 | 2002-11-12 | Smithkline Beecham Corporation | Pharmaceutical formulation of fluticasone propionate |
| DE60019167T2 (en) * | 1999-12-24 | 2006-05-11 | Glaxo Group Ltd., Greenford | PHARMACEUTICAL AEROSOL FORMULATION CONTAINING SALMETEROL AND FLUTICASONE |
| IT1317846B1 (en) | 2000-02-22 | 2003-07-15 | Chiesi Farma Spa | FORMULATIONS CONTAINING AN ANTICOLINERGIC DRUG FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE BRONCOPNEUMOPATHY. |
| MY136453A (en) * | 2000-04-27 | 2008-10-31 | Philip Morris Usa Inc | "improved method and apparatus for generating an aerosol" |
| AU2001257621A1 (en) * | 2000-05-17 | 2001-11-26 | Chrysalis Technologies, Incorporated | Stabilized budesonide solution and method for making same |
| IL152955A0 (en) | 2000-05-22 | 2003-06-24 | Chiesi Farma Spa | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
| US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
| US6701921B2 (en) * | 2000-12-22 | 2004-03-09 | Chrysalis Technologies Incorporated | Aerosol generator having heater in multilayered composite and method of use thereof |
| US6799572B2 (en) | 2000-12-22 | 2004-10-05 | Chrysalis Technologies Incorporated | Disposable aerosol generator system and methods for administering the aerosol |
| US7077130B2 (en) * | 2000-12-22 | 2006-07-18 | Chrysalis Technologies Incorporated | Disposable inhaler system |
| US6681998B2 (en) | 2000-12-22 | 2004-01-27 | Chrysalis Technologies Incorporated | Aerosol generator having inductive heater and method of use thereof |
| US6501052B2 (en) | 2000-12-22 | 2002-12-31 | Chrysalis Technologies Incorporated | Aerosol generator having multiple heating zones and methods of use thereof |
| US6491233B2 (en) | 2000-12-22 | 2002-12-10 | Chrysalis Technologies Incorporated | Vapor driven aerosol generator and method of use thereof |
| ES2222294T3 (en) | 2001-07-02 | 2005-02-01 | Chiesi Farmaceutici S.P.A. | OPTIMIZED FORMULATION OF TOBRAMYCIN FOR ADMINISTRATION IN THE FORM OF AEROSOL. |
| US6568390B2 (en) | 2001-09-21 | 2003-05-27 | Chrysalis Technologies Incorporated | Dual capillary fluid vaporizing device |
| US6640050B2 (en) | 2001-09-21 | 2003-10-28 | Chrysalis Technologies Incorporated | Fluid vaporizing device having controlled temperature profile heater/capillary tube |
| ITRM20010614A1 (en) * | 2001-10-16 | 2003-04-16 | Italchimici S P A | PHARMACEUTICAL PREPARATION OF A BUDESONIDE HYDRO / PROPYLENE SOLUTION AND ITS PREPARATION PROCEDURE. |
| US6681769B2 (en) | 2001-12-06 | 2004-01-27 | Crysalis Technologies Incorporated | Aerosol generator having a multiple path heater arrangement and method of use thereof |
| US6804458B2 (en) | 2001-12-06 | 2004-10-12 | Chrysalis Technologies Incorporated | Aerosol generator having heater arranged to vaporize fluid in fluid passage between bonded layers of laminate |
| US6701922B2 (en) | 2001-12-20 | 2004-03-09 | Chrysalis Technologies Incorporated | Mouthpiece entrainment airflow control for aerosol generators |
| US20030129242A1 (en) * | 2002-01-04 | 2003-07-10 | Bosch H. William | Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer |
| DK1476201T3 (en) * | 2002-02-19 | 2009-03-30 | Resolution Chemicals Ltd | Solvent-based sterilization of steroids |
| GB2389530B (en) * | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| AU2007231727B2 (en) * | 2002-09-03 | 2010-12-16 | Kos Life Sciences, Inc. | Water stabilized medicinal aerosol formulation |
| WO2004032980A1 (en) * | 2002-10-04 | 2004-04-22 | Elan Pharma International Limited | Gamma irradiation of solid nanoparticulate active agents |
| IL152486A0 (en) | 2002-10-25 | 2003-05-29 | Meir Eini | Alcohol-free cosmetic and pharmaceutical foam carrier |
| US8119109B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
| US9211259B2 (en) | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
| US10117812B2 (en) * | 2002-10-25 | 2018-11-06 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
| US7700076B2 (en) | 2002-10-25 | 2010-04-20 | Foamix, Ltd. | Penetrating pharmaceutical foam |
| US20080138296A1 (en) | 2002-10-25 | 2008-06-12 | Foamix Ltd. | Foam prepared from nanoemulsions and uses |
| US8900554B2 (en) | 2002-10-25 | 2014-12-02 | Foamix Pharmaceuticals Ltd. | Foamable composition and uses thereof |
| KR101108439B1 (en) | 2002-10-25 | 2012-01-31 | 포믹스 리미티드 | Cosmetic and pharmaceutical foam |
| US9668972B2 (en) * | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
| US8486376B2 (en) | 2002-10-25 | 2013-07-16 | Foamix Ltd. | Moisturizing foam containing lanolin |
| US7704518B2 (en) | 2003-08-04 | 2010-04-27 | Foamix, Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
| US7820145B2 (en) | 2003-08-04 | 2010-10-26 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
| US9265725B2 (en) | 2002-10-25 | 2016-02-23 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
| US8119150B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Non-flammable insecticide composition and uses thereof |
| EP1596822A2 (en) * | 2003-02-17 | 2005-11-23 | Sun Pharmaceuticals Industries Ltd. | A low dose corticosteroid composition |
| US7575739B2 (en) | 2003-04-28 | 2009-08-18 | Foamix Ltd. | Foamable iodine composition |
| US7842232B2 (en) * | 2003-05-22 | 2010-11-30 | Elan Pharma International, Ltd. | Sterilization of dispersions of nanoparticulate active agents with gamma radiation |
| WO2004112799A1 (en) * | 2003-06-13 | 2004-12-29 | Chrysalis Technologies Incorporated | Methods and apparatus for producing nanoscale particles |
| US8486374B2 (en) | 2003-08-04 | 2013-07-16 | Foamix Ltd. | Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses |
| US8795693B2 (en) | 2003-08-04 | 2014-08-05 | Foamix Ltd. | Compositions with modulating agents |
| AR041873A1 (en) * | 2003-10-30 | 2005-06-01 | Pablo Cassara Srl Lab | A PHARMACEUTICAL FORMULATION IN ADEQUATE AEROSOL FOR ORAL OR NASAL INHALATION CONTAINING GLUCOCORTICOIDS IN A STABLE SOLUTION TO STORAGE; A METHOD FOR STABILIZING FORMULATIONS AND USE OF A STABILIZING AGENT |
| US20070020298A1 (en) * | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid |
| US20070020196A1 (en) * | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid prepared from a unit dose suspension |
| KR20070007076A (en) * | 2003-12-31 | 2007-01-12 | 사이덱스 인크 | INHALANT FORMULATION CONTAINING SULFOALKYL ETHER gamma;-CYCLODEXTRIN AND CORTICOSTEROID |
| US20070020299A1 (en) | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid |
| EP1595531A1 (en) | 2004-05-13 | 2005-11-16 | CHIESI FARMACEUTICI S.p.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
| ATE446581T1 (en) * | 2004-03-12 | 2009-11-15 | Trinity College Dublin | MAGNETORRESISTIVE MEDIUM |
| US20060045850A1 (en) * | 2004-08-30 | 2006-03-02 | Qpharma, Llc | Nasal delivery of cyclodextrin complexes of anti-inflammatory steroids |
| US8679545B2 (en) | 2005-11-12 | 2014-03-25 | The Regents Of The University Of California | Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract |
| US8497258B2 (en) * | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
| US20070160542A1 (en) * | 2005-12-20 | 2007-07-12 | Verus Pharmaceuticals, Inc. | Methods and systems for the delivery of corticosteroids having an enhanced pharmacokinetic profile |
| US20070185066A1 (en) * | 2005-12-20 | 2007-08-09 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids |
| US20070197486A1 (en) * | 2005-12-20 | 2007-08-23 | Verus Pharmaceuticals, Inc. | Methods and systems for the delivery of corticosteroids |
| US20070178049A1 (en) * | 2005-12-20 | 2007-08-02 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids having an enhanced pharmacokinetic profile |
| US20070249572A1 (en) * | 2005-12-20 | 2007-10-25 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids |
| EP1988878A2 (en) * | 2006-02-15 | 2008-11-12 | Tika Läkemedel AB | Sterilization of corticosteroids with reduced mass loss |
| GB0615108D0 (en) * | 2006-07-28 | 2006-09-06 | Glaxo Group Ltd | Novel formulations |
| EP1894559A1 (en) * | 2006-09-01 | 2008-03-05 | PARI Pharma GmbH | Means to solubilise steroids for inhalation |
| US20080260655A1 (en) | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
| ES2493641T3 (en) * | 2007-06-28 | 2014-09-12 | Cydex Pharmaceuticals, Inc. | Nasal administration of aqueous corticosteroid solutions |
| US8636982B2 (en) | 2007-08-07 | 2014-01-28 | Foamix Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
| US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
| US8040246B2 (en) * | 2007-12-04 | 2011-10-18 | Avaya Inc. | Systems and methods for facilitating a first response mission at an incident scene |
| WO2009072007A2 (en) | 2007-12-07 | 2009-06-11 | Foamix Ltd. | Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof |
| WO2010041141A2 (en) | 2008-10-07 | 2010-04-15 | Foamix Ltd. | Oil-based foamable carriers and formulations |
| CA2712120A1 (en) | 2008-01-14 | 2009-07-23 | Foamix Ltd. | Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses |
| US7635773B2 (en) | 2008-04-28 | 2009-12-22 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
| GB0808537D0 (en) * | 2008-05-12 | 2008-06-18 | Archimedes Dev Ltd | Compositions |
| US20090311335A1 (en) * | 2008-06-12 | 2009-12-17 | Scott Jenkins | Combination of a triptan and an nsaid |
| WO2010125470A2 (en) | 2009-04-28 | 2010-11-04 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
| WO2011013009A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
| WO2011013008A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
| US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
| WO2011064631A1 (en) | 2009-10-02 | 2011-06-03 | Foamix Ltd. | Surfactant-free, water-free, foamable compositions and breakable foams and their uses |
| US8174881B2 (en) | 2009-11-24 | 2012-05-08 | Micron Technology, Inc. | Techniques for reducing disturbance in a semiconductor device |
| EP2814849B8 (en) | 2012-02-15 | 2020-03-04 | CyDex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
| RU2747757C2 (en) | 2012-02-28 | 2021-05-13 | Сидекс Фармасьютикалс, Инк. | Compositions of alkylated cyclodextrin and methods of their preparation and application |
| MY181829A (en) | 2012-10-22 | 2021-01-08 | Cydex Pharmaceuticals Inc | Alkylated cyclodextrin compositions and processes for preparing and using the same |
| ES2622372T3 (en) * | 2012-11-09 | 2017-07-06 | Scidose Llc | Enema composition for treatment of ulcerative colitis that has long-term stability |
| TW201505635A (en) | 2013-05-21 | 2015-02-16 | Salix Pharmaceuticals Inc | Methods of treating ulcerative colitis |
| WO2015109201A1 (en) | 2014-01-17 | 2015-07-23 | Nephron Pharmaceuticals Corporation | Budesonide cyclodextrin formulation |
| PT3183295T (en) | 2014-08-22 | 2023-11-03 | Cydex Pharmaceuticals Inc | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
| SE540537C2 (en) | 2015-07-03 | 2018-09-25 | Hallberg Per | Metod och anordning för att reducera flöde av jordluft till inomhusluft i en byggnad |
| MX2020012139A (en) | 2016-09-08 | 2021-01-29 | Vyne Pharmaceuticals Inc | Compositions and methods for treating rosacea and acne. |
| US20190351060A1 (en) | 2016-12-16 | 2019-11-21 | Ferring B.V. | Rectal Foam Formulations |
| US11464733B2 (en) | 2016-12-28 | 2022-10-11 | Dr. Falk Pharma Gmbh | Enema for rectal application |
| AU2018318123A1 (en) | 2017-08-15 | 2020-03-19 | Nephron Pharmaceuticals Corporation | Aqueous nebulization composition |
| RU2738658C1 (en) | 2020-03-18 | 2020-12-15 | Всеволод Иванович Киселёв | MEDICINAL AGENT IN FORM OF COMPLEX OF 3,3'-DIINDOLYLMETHANE AND β-CYCLODEXTRIN, METHOD FOR PREPARING THEREOF AND METHOD OF TREATING CERVICAL NEOPLASIA USING THEREOF |
| US11896719B2 (en) | 2022-01-24 | 2024-02-13 | Calliditas Therapeutics Ab | Pharmaceutical compositions |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4383992A (en) * | 1982-02-08 | 1983-05-17 | Lipari John M | Water-soluble steroid compounds |
| IT1243379B (en) * | 1990-07-27 | 1994-06-10 | Giuliani Spa | PHARMACEUTICAL COMPOSITION SUITABLE FOR RECTAL ADMINISTRATION OF ACTIVE PRINCIPLES WHICH EXPLICATE A MEDICATION ACTION AT THE LEVEL OF THE COLON, PREVALENTLY TOPICAL |
| CA2153681C (en) * | 1993-01-21 | 2004-05-25 | Marc Karel Jozef Francois | Topical ketoconazole compositions |
| DE4340057A1 (en) * | 1993-11-24 | 1995-06-01 | Falk Pharma Gmbh | Budesonide drugs to improve enteral fluid absorption, especially after postoperative conditions |
| FR2713486B1 (en) * | 1993-12-14 | 1996-02-09 | Scophysa | New compositions for foams, in particular rectal foams, and foams thus obtained. |
-
1994
- 1994-12-27 DE DE4446891A patent/DE4446891A1/en not_active Ceased
-
1995
- 1995-12-19 JP JP52012196A patent/JP3421348B2/en not_active Expired - Lifetime
- 1995-12-19 WO PCT/DE1995/001847 patent/WO1996019969A1/en not_active Application Discontinuation
- 1995-12-19 EP EP95942642A patent/EP0794767B1/en not_active Revoked
- 1995-12-19 ES ES95942642T patent/ES2120247T3/en not_active Expired - Lifetime
- 1995-12-19 DE DE59502928T patent/DE59502928D1/en not_active Revoked
- 1995-12-19 DK DK95942642T patent/DK0794767T3/en active
- 1995-12-19 AT AT95942642T patent/ATE168556T1/en not_active IP Right Cessation
- 1995-12-19 CA CA002205305A patent/CA2205305C/en not_active Expired - Lifetime
-
1997
- 1997-06-27 US US08/860,136 patent/US5914122A/en not_active Expired - Lifetime
-
1998
- 1998-08-12 GR GR980401810T patent/GR3027632T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0794767A1 (en) | 1997-09-17 |
| US5914122A (en) | 1999-06-22 |
| ATE168556T1 (en) | 1998-08-15 |
| DK0794767T3 (en) | 1999-02-01 |
| GR3027632T3 (en) | 1998-11-30 |
| CA2205305A1 (en) | 1996-07-04 |
| DE59502928D1 (en) | 1998-08-27 |
| EP0794767B1 (en) | 1998-07-22 |
| ES2120247T3 (en) | 1998-10-16 |
| DE4446891A1 (en) | 1996-07-04 |
| JP3421348B2 (en) | 2003-06-30 |
| JPH10511364A (en) | 1998-11-04 |
| WO1996019969A1 (en) | 1996-07-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2205305C (en) | Stable budesonide solutions, method of preparing them and use of these solutions as enema preparations and pharmaceutical foams | |
| BE1005085A3 (en) | Drugs. | |
| TWI544922B (en) | High concentration olopatadine ophthalmic composition | |
| PT88564B (en) | PROCESS FOR THE PREPARATION OF A DELAYED LIBERTACAO ETHODOLAC DOSE FORM | |
| JPS61500788A (en) | Pharmaceutical preparations containing water-labile or slightly soluble drugs and methods for their production | |
| CN104027299A (en) | Itraconazole temperature-sensitive type gel preparation as well as preparation method and application thereof | |
| JPH0534345B2 (en) | ||
| JPH05213757A (en) | Aqueous solution | |
| US20070099883A1 (en) | Anhydrous mometasone furoate formulation | |
| US20100105750A1 (en) | Stable metronidazole gel formulations | |
| US20060193783A1 (en) | Low dose corticosteroid composition | |
| KR20180110184A (en) | Novel Pharmaceutical Formulation Comprising NSAID and Cyclodextrin | |
| JP2009500387A (en) | Fentanyl formulation containing essential oil | |
| TWI246926B (en) | Pharmaceutical dronedarone composition for parenteral administration | |
| CN103079559A (en) | Formulations including amiodarone and salts thereof and methods of their manufacture and use | |
| JP2022173567A (en) | Enemas | |
| US20090325917A1 (en) | Pharmaceutical Compositions and Nasal Spray Incorporating Anhydrous Mometasone Furoate | |
| WO2018219747A1 (en) | Composition for treating or preventing climacteric disorders | |
| JPH0637388B2 (en) | Aqueous solution | |
| TW200402307A (en) | Nasal composition | |
| WO2016154240A1 (en) | Aqueous solution of polymers | |
| JPS6245524A (en) | Sodium phenytoin aqueous medicine | |
| JP3911125B2 (en) | Method for producing a solution for nasal spray containing sex hormone and cyclodextrin | |
| AU2017265087B2 (en) | Pharmaceutical composition of sildenafil citrate in the form of a suspension for oral use | |
| US3524916A (en) | Griseofulvin-ethylene glycol monosalicylate compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20151221 |