CA1063936A - Preparation of amorphous solid of macrolide antibiotics - Google Patents
Preparation of amorphous solid of macrolide antibioticsInfo
- Publication number
- CA1063936A CA1063936A CA249,607A CA249607A CA1063936A CA 1063936 A CA1063936 A CA 1063936A CA 249607 A CA249607 A CA 249607A CA 1063936 A CA1063936 A CA 1063936A
- Authority
- CA
- Canada
- Prior art keywords
- cellulose
- amorphous solid
- macrolide
- antibiotic
- macrolide antibiotic
- 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
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Amorphous solids of macrolide antibiotics which are stable with the passage of time are prepared by dissolving a macrolide antibiotic and a cellulose polymer as a stabilizing substance in a volatile organic solvent and spray drying the resulting solution.
Amorphous solids of macrolide antibiotics which are stable with the passage of time are prepared by dissolving a macrolide antibiotic and a cellulose polymer as a stabilizing substance in a volatile organic solvent and spray drying the resulting solution.
Description
BACKGROUND OF THE INVENTION
______________________~____ FIELD OF THE: INVENTION
______________________ This invention relates to a process for preparing amor-phous solid macrolide antibiotics which are stable with the passage of time.
DESCRIPTION OF THE PRIOR ART
A substance which i sparingly soluble in water generally has the property that crystals thereof differ in solubility from the amorphous solid from thereof, and the latter has a higher solubility. This difference in solubility is of great significance in pharmaceutical formulations. For example, macrolide anti-biotics (e.g., midecamycin, kitasamycin, josamycin, erthromycin, spiramycin, or derivatives thereof) are sparingly water soluble substances, and in orally administrable formulations such as tablets, capsules or dry syrups of these substances, the use of ; the amorphous solid form thereof having better solubility, can lead to full effectiveness of these antibiotics.
Since, however, amorphous solids are inherently at a high energy level, they are unstable and apt to change into the crystal form with the passage of time. For example, the ~apanese language publication "Method of Designing Pharmaceutical Formula-tions (2), First Part" (Lectures in Fundamentals of Development of Pharmaceuticals, Vol. IX, edited by Masashi Nogami and Kyosuke Tsuda, published by Chijin Shokan) states: "Amorphous solids frequently assume this state by lyophilization, rapid cooling of a molten liquid, or the co-presence of impurities (a kind of plasticization), but are apt to be converted to a stable crystal-line state".
Attempts to obtain amorphous solids of macrolide anti-biotics (e.g., midecamycin, 9-acetyl-3"-acetylmidecam~cin, ~itasa-mycin, erythromycin, or josamycin) by ordinary techniques (e.g., lyophilization or the rapid cooling of a molten liquid) result in products containing crystals, or products which are xeadily converted to crystals with the passage of time, and it is difficult to obtain crystal-free amorphous solids which are stable with the passage of time.
Conventional techniques for the spray drying of macrolide antibiotics are disclosed, for example, in Japanese Patent Pub-lications (OPI) 81526/74, 133513/74 and 132216/74.
Japanese Patent Publication (OPI) 81526/74 discloses a process for preparing a coated antibiotic for oral administration free from a bitter taste and a reduction in its effective con-centration in blood which comprises dissolving a macrolide anti-biotic in a solution or dispersion in an inert volatile organic solvent of a wall forming polymer selected from the group con-sisting of polyvinyl acetal diethylaminoacetate, cellulose acetate dibutylaminohydroxypropyl ether, a dimethylaminoethyl methacrylate/
methacrylate copolymer and ethyl cellulose and at least one material selected from the group consisting of waxes, higher fatty acids and insoluble salts of higher fatty acids, and spray drying the resulting solution.
Japanese Patent Publication (OPI) 133513/74, on the other hand, discloses a process for preparing a coated antibiotic for oral administration free from a bitter taste and a reduction in its effective concentration in blood which has a fine particle size and excellent water repellency, which comprises dissolving the macrolide antibiotic in a solution or dispersion in the above organic solvent of the wall forming polymer and at least one ,~.' ~ .
, ~ , ~, ~
material selected from higher fatty acids, ~laxes, and insoluble salts of higher fatty acids and also a non-toxic mineral oil, vegetable oil, animal oil, surfactant or defoamer soluble in the above organic solvent and having an H.L.B. of not more than about 5, and spray drying the resulting solution.
Furthermore, Japanese Patent Publication (OPI) 132216/74 discloses a process for producing a coated macrolide antibiotic suitable for oral administration which has a good shape and is free from bitterness and a reduction in its concentration in blood, the process comprising dissolving a macrolide antibiotic in a solution or dispersion in an inert volatile organic solvent of a wall forming material selected from the group consisting of a styrene/maleic acid copolymer, higher fatty acids, higher fatty acid derivatives and water insoluble salts of higher fatty acids, and spray drying the resulting solution.
The invention of Japanese Patent Publication (OPI) 81526/74 requires at least one coating substance selected from the group of wall forming polymers and the group of waxes, higher fatty acids and insoluble salts of higher fatty acids.
In the invention of Japanese Patent Publication (OPI) 133513/74, a non-toxic mineral oil, vegetable oil, animal oil, surfactant or defoamer having an H.L.B. of not more than about 5 is further used as a coating material in addition to the coating material used in the invention of Japanese Patent Publication (OPI) 81526/74.
The invention of Japanese Patent Publication (OPI) 132216/74 is the same as that of Japanese Patent Publication (OPI) 81526/74 except that a styrene/maleic acid copolymer is used as the wall forming polymer. The amount of such coating substances is equal to, or larger than,that of the macrolide antibiotic, and I they are regarded as effective for the prevention of the bitter-ness of the antibiotic.
SUMMARY OF TH~ INVENTION
________________________ Our extensive investigations in an attempt to provide a process for producing amorphous solids free from crystals and having good sta~ility with the passage of time led to the dis-covery that amorphous solids of macrolide antibiotics which are free from crystals and have good stability with the passage of time can be obtained by spray drying a solution in a volatile organic solvent of a macrolide antibiotic and at least one cellulose polymer.
Accoridngly, it is an object of this invention to pro-vide a process for preparing amorphous solids of macrolide anti-biotics which are stable with the passage of time.
BRIEF DESCRIPTION OF THE DRAWINGS
_________________________________ Figure 1 is a microphotogarph of crystals of 9-acetyl-3"-acetylmidecamycin (10 x 10).
Figure 2 is a microphotograph of an amorphous solid (10 x 10) of 9-acetyl-3"-acetylmidecamycin obtained by the process of this invention using ethyl cellulose as a stabilizing substance.
Figure 3 is an X-ray diffraction pattern of the crystals of 9-acetyl-3"-acetylmidecamycin.
Figure 4 is an X-ray diffraction pattern of the amorphous solid of 9-acetyl-3"-acetylmidecamycin immediately after prepara-tion by the process of this invention using ethyl cellulose as a stabilizing substance.
Figure 5 is an X-ray diffraction pattern of the amorphous solid shown in Figure 4 after storage for 5 weeks at Ei~ur~ 6 is an X-xay diffraction pattern ~f an ~morphous solid of 9-acetyl-3"-acetylmidecam~cin immediately after prepara-tion wlthout using the stabilizing substance of the present inventlon.
Figure 7 is an X-ray diffraction pa-ttern of the amorphous solid shown in Figure 6 after storage for 5 weeks at 60 C.
DETAILED DESCRIPTION OF THE INVENTION
_____________________________________ The present invention provides a process for preparing amorphous solids of macrolide antibiotics having good stability with the passage of time, that is, the capability not to convert to the crystalline form with the passage of time, which comprises spray drying a solution in a volatile organic solvent of a macro-lide antibiotic and at least one cellulose polymer.
The process of the present invention is basically different from the three patent publications cited above in that it does not require the waxes, higher fatty acids, insoluble salts of higher fatty acids, mineral oil, vegetable oil, animal oil, surfactant, or defoamer required therein.
For example, an amorphous solid obtained by spray drying a solution of 10 g of 9-acetyl-3"-acetylmidecamycin and 2 g of ethyl cellulose in 100 g of dichloromethane in accordance with the process of this invention does not contain any crystals, and main-tains its state even after storage at 60C for 5 weeks. In con-trast, a product obtained by spray drying a solution of only the antibiotic in the solvent contains a small amount of crystals even immediately after preparation, and is almost entirely crystallized upon storage at 60C for 5 weeks. The presence of crystals was evaluated by the presence or absence of polarized ,, , : , , , ' ' " ' ' light through a microscope and ~ X-ray diffraction. The results of the above analysis are shown in Figures 1 to 7 of the accompanying drawings.
Using an experimental animal ~a domesticated rabbit with a body weight of 3.3 to 3.6 kg), the concentration in the blood of the rabbit of amorphous solid 9-acetyl-3~-acetylmidecamy-cin obtained by the process of this invertion using ethyl cellulose as a stabilizing substance was measured in comparison with that of crystalline 9-acetyl-3"-acetylmidecamycin. The results are shown 10 in Table 1 below.
These results demonstrate that the concentration in the blood of the amorphous solid (which is stable with the passage of time and is obtained by the process of this invention) as its maximum shows about twice as large a value as that of the crystal-line 9-acetyl-3"-acetylmidecamycin, indicating very good absorption.
TABLE
200 mg (titer)/kg Oral administration Assay: Sarcina lutea ATCC 9341 Cylinder-plate method Crystalline 9-acetyl-3"-acetylmidecamycin ~ Time (hours) Rabbit No 0.5 1 2 4 8 1 1.6 2.8 3.2 1.5 0
______________________~____ FIELD OF THE: INVENTION
______________________ This invention relates to a process for preparing amor-phous solid macrolide antibiotics which are stable with the passage of time.
DESCRIPTION OF THE PRIOR ART
A substance which i sparingly soluble in water generally has the property that crystals thereof differ in solubility from the amorphous solid from thereof, and the latter has a higher solubility. This difference in solubility is of great significance in pharmaceutical formulations. For example, macrolide anti-biotics (e.g., midecamycin, kitasamycin, josamycin, erthromycin, spiramycin, or derivatives thereof) are sparingly water soluble substances, and in orally administrable formulations such as tablets, capsules or dry syrups of these substances, the use of ; the amorphous solid form thereof having better solubility, can lead to full effectiveness of these antibiotics.
Since, however, amorphous solids are inherently at a high energy level, they are unstable and apt to change into the crystal form with the passage of time. For example, the ~apanese language publication "Method of Designing Pharmaceutical Formula-tions (2), First Part" (Lectures in Fundamentals of Development of Pharmaceuticals, Vol. IX, edited by Masashi Nogami and Kyosuke Tsuda, published by Chijin Shokan) states: "Amorphous solids frequently assume this state by lyophilization, rapid cooling of a molten liquid, or the co-presence of impurities (a kind of plasticization), but are apt to be converted to a stable crystal-line state".
Attempts to obtain amorphous solids of macrolide anti-biotics (e.g., midecamycin, 9-acetyl-3"-acetylmidecam~cin, ~itasa-mycin, erythromycin, or josamycin) by ordinary techniques (e.g., lyophilization or the rapid cooling of a molten liquid) result in products containing crystals, or products which are xeadily converted to crystals with the passage of time, and it is difficult to obtain crystal-free amorphous solids which are stable with the passage of time.
Conventional techniques for the spray drying of macrolide antibiotics are disclosed, for example, in Japanese Patent Pub-lications (OPI) 81526/74, 133513/74 and 132216/74.
Japanese Patent Publication (OPI) 81526/74 discloses a process for preparing a coated antibiotic for oral administration free from a bitter taste and a reduction in its effective con-centration in blood which comprises dissolving a macrolide anti-biotic in a solution or dispersion in an inert volatile organic solvent of a wall forming polymer selected from the group con-sisting of polyvinyl acetal diethylaminoacetate, cellulose acetate dibutylaminohydroxypropyl ether, a dimethylaminoethyl methacrylate/
methacrylate copolymer and ethyl cellulose and at least one material selected from the group consisting of waxes, higher fatty acids and insoluble salts of higher fatty acids, and spray drying the resulting solution.
Japanese Patent Publication (OPI) 133513/74, on the other hand, discloses a process for preparing a coated antibiotic for oral administration free from a bitter taste and a reduction in its effective concentration in blood which has a fine particle size and excellent water repellency, which comprises dissolving the macrolide antibiotic in a solution or dispersion in the above organic solvent of the wall forming polymer and at least one ,~.' ~ .
, ~ , ~, ~
material selected from higher fatty acids, ~laxes, and insoluble salts of higher fatty acids and also a non-toxic mineral oil, vegetable oil, animal oil, surfactant or defoamer soluble in the above organic solvent and having an H.L.B. of not more than about 5, and spray drying the resulting solution.
Furthermore, Japanese Patent Publication (OPI) 132216/74 discloses a process for producing a coated macrolide antibiotic suitable for oral administration which has a good shape and is free from bitterness and a reduction in its concentration in blood, the process comprising dissolving a macrolide antibiotic in a solution or dispersion in an inert volatile organic solvent of a wall forming material selected from the group consisting of a styrene/maleic acid copolymer, higher fatty acids, higher fatty acid derivatives and water insoluble salts of higher fatty acids, and spray drying the resulting solution.
The invention of Japanese Patent Publication (OPI) 81526/74 requires at least one coating substance selected from the group of wall forming polymers and the group of waxes, higher fatty acids and insoluble salts of higher fatty acids.
In the invention of Japanese Patent Publication (OPI) 133513/74, a non-toxic mineral oil, vegetable oil, animal oil, surfactant or defoamer having an H.L.B. of not more than about 5 is further used as a coating material in addition to the coating material used in the invention of Japanese Patent Publication (OPI) 81526/74.
The invention of Japanese Patent Publication (OPI) 132216/74 is the same as that of Japanese Patent Publication (OPI) 81526/74 except that a styrene/maleic acid copolymer is used as the wall forming polymer. The amount of such coating substances is equal to, or larger than,that of the macrolide antibiotic, and I they are regarded as effective for the prevention of the bitter-ness of the antibiotic.
SUMMARY OF TH~ INVENTION
________________________ Our extensive investigations in an attempt to provide a process for producing amorphous solids free from crystals and having good sta~ility with the passage of time led to the dis-covery that amorphous solids of macrolide antibiotics which are free from crystals and have good stability with the passage of time can be obtained by spray drying a solution in a volatile organic solvent of a macrolide antibiotic and at least one cellulose polymer.
Accoridngly, it is an object of this invention to pro-vide a process for preparing amorphous solids of macrolide anti-biotics which are stable with the passage of time.
BRIEF DESCRIPTION OF THE DRAWINGS
_________________________________ Figure 1 is a microphotogarph of crystals of 9-acetyl-3"-acetylmidecamycin (10 x 10).
Figure 2 is a microphotograph of an amorphous solid (10 x 10) of 9-acetyl-3"-acetylmidecamycin obtained by the process of this invention using ethyl cellulose as a stabilizing substance.
Figure 3 is an X-ray diffraction pattern of the crystals of 9-acetyl-3"-acetylmidecamycin.
Figure 4 is an X-ray diffraction pattern of the amorphous solid of 9-acetyl-3"-acetylmidecamycin immediately after prepara-tion by the process of this invention using ethyl cellulose as a stabilizing substance.
Figure 5 is an X-ray diffraction pattern of the amorphous solid shown in Figure 4 after storage for 5 weeks at Ei~ur~ 6 is an X-xay diffraction pattern ~f an ~morphous solid of 9-acetyl-3"-acetylmidecam~cin immediately after prepara-tion wlthout using the stabilizing substance of the present inventlon.
Figure 7 is an X-ray diffraction pa-ttern of the amorphous solid shown in Figure 6 after storage for 5 weeks at 60 C.
DETAILED DESCRIPTION OF THE INVENTION
_____________________________________ The present invention provides a process for preparing amorphous solids of macrolide antibiotics having good stability with the passage of time, that is, the capability not to convert to the crystalline form with the passage of time, which comprises spray drying a solution in a volatile organic solvent of a macro-lide antibiotic and at least one cellulose polymer.
The process of the present invention is basically different from the three patent publications cited above in that it does not require the waxes, higher fatty acids, insoluble salts of higher fatty acids, mineral oil, vegetable oil, animal oil, surfactant, or defoamer required therein.
For example, an amorphous solid obtained by spray drying a solution of 10 g of 9-acetyl-3"-acetylmidecamycin and 2 g of ethyl cellulose in 100 g of dichloromethane in accordance with the process of this invention does not contain any crystals, and main-tains its state even after storage at 60C for 5 weeks. In con-trast, a product obtained by spray drying a solution of only the antibiotic in the solvent contains a small amount of crystals even immediately after preparation, and is almost entirely crystallized upon storage at 60C for 5 weeks. The presence of crystals was evaluated by the presence or absence of polarized ,, , : , , , ' ' " ' ' light through a microscope and ~ X-ray diffraction. The results of the above analysis are shown in Figures 1 to 7 of the accompanying drawings.
Using an experimental animal ~a domesticated rabbit with a body weight of 3.3 to 3.6 kg), the concentration in the blood of the rabbit of amorphous solid 9-acetyl-3~-acetylmidecamy-cin obtained by the process of this invertion using ethyl cellulose as a stabilizing substance was measured in comparison with that of crystalline 9-acetyl-3"-acetylmidecamycin. The results are shown 10 in Table 1 below.
These results demonstrate that the concentration in the blood of the amorphous solid (which is stable with the passage of time and is obtained by the process of this invention) as its maximum shows about twice as large a value as that of the crystal-line 9-acetyl-3"-acetylmidecamycin, indicating very good absorption.
TABLE
200 mg (titer)/kg Oral administration Assay: Sarcina lutea ATCC 9341 Cylinder-plate method Crystalline 9-acetyl-3"-acetylmidecamycin ~ Time (hours) Rabbit No 0.5 1 2 4 8 1 1.6 2.8 3.2 1.5 0
2 3.6 4.9 3.8 2.8 0
3 3.3 4.2 6.2 2.0 0 X 2.8 4.0 4.4 2.1 0 Amorphous solid 9-acetyl-3"-acetylmidecamycin using ethyl cell~lose as a stabilizing substance Time ~hours) Rabbit NoØ5 1 2 4 8 1 12.2 14.5 6.9 2.5 0 2 4.0 6.6 4.8 2.0 0 3 5.8 6.6 8.4 2.4 0 x 7.3 9.2 6.7 2.3 0 Units of the values: ,ug (titer)/m ¢
The cellulose polymer used as a stabilizing substance in this invention may be any one conventionally used in the pharmaceutical arts and suitable includes, for example, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropylmethyl cellulose phthalate. The amount of the cellulose polymer added is not limited in particular, and it is usually about 5 to about 40%, preferably about 10 to about 30% (by weight), based on the macrolide antibiotic. The , molecular weight of cellulose polymers is preferably in a range of above about 1,000.
The solvent used in this invention may be any of volatile organic solvents such as can dissolve the above mentioned polymer and the macrolide antibiotics and volatilize during spray drying; chloroform, dichloroethane, l,l,l,-tri-chloroethane. The dichloromethane and trichloroethane are especially preferred.
As is well known, a macrolide antibiotic is an -antibiotic which contains a macrocyclic lactone ring and an amino sugar and a carbonyl group bonded thereto through a glycoside linkage as a basic structure. Thus, all antibiotics which are embraced within the above concept and are soluble in :; the volatile organic solvents described can be used in the "
, s "
resent invention. Examples of the macrolide antibiotics ar~
midecamycin, kit~samycin, josamycin, erythromycin, malidemycin, spiramycin, and derivatives of these.
The concentration of the macrolide antibiotic in the volatile organic solvent is not limited in particular.
Usually, suitable concentrations are about 5 to about 50%, preferably about 10 to 30%.
The spray drying in accordance with this invention can be carried out using conventional spray driers ~e.g., of the nozzle type, disc type, or jet type) by the procedures inherent to the use of these devices.
It should be noted, in this regard, that the dosage rate, etc., of the active ingredients of the compositions of the present invention is identical to those for conventional macrolide antibiotics.
Spray drying of a solution of the macrolide antibiotic and the cellulose polymer as a stabilizing substance in a suitable solvent provides an amorphous solid of the antibiotic which is free from crystals and is stable with the passage of time.
As one skilled in the art will appreciate, the pressure of spray drying is in accordance with conventional spray drying techniques as such are practiced in the art.
Generally, on a commercial scale, the pressure of spray drying is atmospheric pressure and the temperature is above about 60C
but, of course, below any temperature which would degrade or decompose any of the materials being sprayed dried. The time of spray drying, of course, is considerably short, and in accordance with times as are conventionally used in the art for spray drying materials.
The following Examples illustrate the present inve~tion.
The pressure cmployed for spray drying is atmospheric throughout.
EXAMæLE 1 10 g of 9-acetyl-3"-acetylmidecamycin was dissolved in 200 m ~ of a chloroform solution containing 4 g of hydroxy-propylmethyl cellulose phthalate (mean molecular weight: about 1,000) as a stabilizing substance. The resulting solution was dried at 100C and at atmospheric pressure using a spray drier of the disc type for about 10 minutes. A stable amorphous solid was obtained.
When this product was stored at 60C for 6 weeks, it remained as an amorphous solid.
An amorphous solid of the same antibiotic prepared by spray drying in the above manner except that the stabilizing substance was not used became almost entirely crystalline after storage at 60C for 2 weeks.
Evaluation of the crystals was determined by the presence or absence of polarized light through a microscope.
The same evaluating method was used in the following Examples.
10 g of 9-acetyl-3"-acetylmidecamycin and 1 g of hydroxypropylmethyl cellulose ~mean molecular weight: about -1,000) and 1 g of ethyl cellulose (mean molecular weight:
about 1,000) as a stabilizing substance were dissolved in 250 m of 1,1,1-trichloroethane. The resulting solution was spray dried at about 130C for about 10 minutes using a spray drier of the jet type to provide a stable amorphous solid. When this product was stored at 60C for 2 months, it still remained as an amorphous solid.
-: _ g _ :
-` 1063936 An amorphous solid obtain~d in the above manner except that the stabilizing substances were not used became almost entirely crystalline after storage at 60C for 1 week.
5 g of kitasamycin was dissolved in 150 m~ of a chloroform solution containing 0.3 g of hydroxypropyl cellulose (mean molecular weight: about 1,000) as a stabilizing substance.
The resulting solution was spray dried at about 100C for about 10 minutes using a spray drier of the disc type to provide a stable amorphous solid. When this product was stored at 60C
for 4 months, it still remained as an amorphous solid.
An amorphous solid obtained in the above manner except that the stabilizing substance was not used became partly crystalline after storage for one month at 60C.
3 g of josamycin was disSolved in 300 m~ of chloroform - containing 0.1 g of ethyl cellulose (mean molecular weight:
about 1,000) and 0.05 g of hydroxypropyl cellulose (mean molecular weight: about 1,000). The resulting solution was spray dried at about 130C for about 10 minutes using a spray drier of the jet type to provide a stable amorphous solid.
When this product was stored at 60C for 1 month, it still remained as an amorphous solid.
An amorphous solid obtained in the above manner except that the stabilizing substances were not added became partly crystalline after storage at 60C for 2 weeks.
10 g of midecamycin was dissolved in 300 m of benzene, and 0.5 g of hydroxypropylmethyl cellulose (mean molecular weight: about 1,000) was added to the solution. The ~, , ,~ . .
resulting solution is spray dried at about 150C for about 10 minutes using a spray drier of the jet type to provide a stable amorphous solid. When this product was stored at 60C for 2 months, it still remained as an amorphous solid.
An amorphous solid obtained in the above manner except that the stabilizing substance was not added became partly crystalline after storage at 60C for 2 weeks.
lO g of 9-acetyl-3"-acetylmidecamycin was dissolved in 200 m~ of dichloromethane containing 1.5 g of ethyl cellulose (mean molecular weight: about l,000). The resulting solution was spray dried at about 100C for about lO minutes using a spray drier ofthe jet type. When this product was stored at 60C for 7 months, it still remained as an amorphous solid.
~ n amorphous solid obtained in the above manner except that the stabilizing substance was not added became almost entirely crystalline after storage at 60C for 2 weeks.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be ~ -apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. ;
' -.
, .,
The cellulose polymer used as a stabilizing substance in this invention may be any one conventionally used in the pharmaceutical arts and suitable includes, for example, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropylmethyl cellulose phthalate. The amount of the cellulose polymer added is not limited in particular, and it is usually about 5 to about 40%, preferably about 10 to about 30% (by weight), based on the macrolide antibiotic. The , molecular weight of cellulose polymers is preferably in a range of above about 1,000.
The solvent used in this invention may be any of volatile organic solvents such as can dissolve the above mentioned polymer and the macrolide antibiotics and volatilize during spray drying; chloroform, dichloroethane, l,l,l,-tri-chloroethane. The dichloromethane and trichloroethane are especially preferred.
As is well known, a macrolide antibiotic is an -antibiotic which contains a macrocyclic lactone ring and an amino sugar and a carbonyl group bonded thereto through a glycoside linkage as a basic structure. Thus, all antibiotics which are embraced within the above concept and are soluble in :; the volatile organic solvents described can be used in the "
, s "
resent invention. Examples of the macrolide antibiotics ar~
midecamycin, kit~samycin, josamycin, erythromycin, malidemycin, spiramycin, and derivatives of these.
The concentration of the macrolide antibiotic in the volatile organic solvent is not limited in particular.
Usually, suitable concentrations are about 5 to about 50%, preferably about 10 to 30%.
The spray drying in accordance with this invention can be carried out using conventional spray driers ~e.g., of the nozzle type, disc type, or jet type) by the procedures inherent to the use of these devices.
It should be noted, in this regard, that the dosage rate, etc., of the active ingredients of the compositions of the present invention is identical to those for conventional macrolide antibiotics.
Spray drying of a solution of the macrolide antibiotic and the cellulose polymer as a stabilizing substance in a suitable solvent provides an amorphous solid of the antibiotic which is free from crystals and is stable with the passage of time.
As one skilled in the art will appreciate, the pressure of spray drying is in accordance with conventional spray drying techniques as such are practiced in the art.
Generally, on a commercial scale, the pressure of spray drying is atmospheric pressure and the temperature is above about 60C
but, of course, below any temperature which would degrade or decompose any of the materials being sprayed dried. The time of spray drying, of course, is considerably short, and in accordance with times as are conventionally used in the art for spray drying materials.
The following Examples illustrate the present inve~tion.
The pressure cmployed for spray drying is atmospheric throughout.
EXAMæLE 1 10 g of 9-acetyl-3"-acetylmidecamycin was dissolved in 200 m ~ of a chloroform solution containing 4 g of hydroxy-propylmethyl cellulose phthalate (mean molecular weight: about 1,000) as a stabilizing substance. The resulting solution was dried at 100C and at atmospheric pressure using a spray drier of the disc type for about 10 minutes. A stable amorphous solid was obtained.
When this product was stored at 60C for 6 weeks, it remained as an amorphous solid.
An amorphous solid of the same antibiotic prepared by spray drying in the above manner except that the stabilizing substance was not used became almost entirely crystalline after storage at 60C for 2 weeks.
Evaluation of the crystals was determined by the presence or absence of polarized light through a microscope.
The same evaluating method was used in the following Examples.
10 g of 9-acetyl-3"-acetylmidecamycin and 1 g of hydroxypropylmethyl cellulose ~mean molecular weight: about -1,000) and 1 g of ethyl cellulose (mean molecular weight:
about 1,000) as a stabilizing substance were dissolved in 250 m of 1,1,1-trichloroethane. The resulting solution was spray dried at about 130C for about 10 minutes using a spray drier of the jet type to provide a stable amorphous solid. When this product was stored at 60C for 2 months, it still remained as an amorphous solid.
-: _ g _ :
-` 1063936 An amorphous solid obtain~d in the above manner except that the stabilizing substances were not used became almost entirely crystalline after storage at 60C for 1 week.
5 g of kitasamycin was dissolved in 150 m~ of a chloroform solution containing 0.3 g of hydroxypropyl cellulose (mean molecular weight: about 1,000) as a stabilizing substance.
The resulting solution was spray dried at about 100C for about 10 minutes using a spray drier of the disc type to provide a stable amorphous solid. When this product was stored at 60C
for 4 months, it still remained as an amorphous solid.
An amorphous solid obtained in the above manner except that the stabilizing substance was not used became partly crystalline after storage for one month at 60C.
3 g of josamycin was disSolved in 300 m~ of chloroform - containing 0.1 g of ethyl cellulose (mean molecular weight:
about 1,000) and 0.05 g of hydroxypropyl cellulose (mean molecular weight: about 1,000). The resulting solution was spray dried at about 130C for about 10 minutes using a spray drier of the jet type to provide a stable amorphous solid.
When this product was stored at 60C for 1 month, it still remained as an amorphous solid.
An amorphous solid obtained in the above manner except that the stabilizing substances were not added became partly crystalline after storage at 60C for 2 weeks.
10 g of midecamycin was dissolved in 300 m of benzene, and 0.5 g of hydroxypropylmethyl cellulose (mean molecular weight: about 1,000) was added to the solution. The ~, , ,~ . .
resulting solution is spray dried at about 150C for about 10 minutes using a spray drier of the jet type to provide a stable amorphous solid. When this product was stored at 60C for 2 months, it still remained as an amorphous solid.
An amorphous solid obtained in the above manner except that the stabilizing substance was not added became partly crystalline after storage at 60C for 2 weeks.
lO g of 9-acetyl-3"-acetylmidecamycin was dissolved in 200 m~ of dichloromethane containing 1.5 g of ethyl cellulose (mean molecular weight: about l,000). The resulting solution was spray dried at about 100C for about lO minutes using a spray drier ofthe jet type. When this product was stored at 60C for 7 months, it still remained as an amorphous solid.
~ n amorphous solid obtained in the above manner except that the stabilizing substance was not added became almost entirely crystalline after storage at 60C for 2 weeks.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be ~ -apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. ;
' -.
, .,
Claims (11)
1. A process for preparing amorphous solid of macrolide antibiotics which are stable with the passage of time, said process comprising spray drying a solution in a volatile organic solvent of a macrolide antibiotic and at least one cellulose polymer, the concentration of the microlide antibiotic in the solvent being about 5 to about 50% by weight, and the concen-tration of the cellulose polymer is about 5 to about 40% by weight based on the macrolide antibiotic.
2. The process of Claim 1, wherein said cellulose polymer is selected from the group consisting of ethyl cellulose, hydr-oxypropyl cellulose, and hydroxypropylmethyl cellulose.
3. The process of Claim 1, wherein said solvent is dichloromethane, trichloroethane, or chloroform.
4. The process of Claim 2, wherein said solvent is dichloromethane, trichloromethane or chloroform.
5. The process of Claim 2, wherein the amount of said cellulose polymer is about 5% to about 40% by weight, based on the macrolide antibiotic.
6. The process of Claim 3, wherein the concentration of macrolide antibiotic in the solvent is about 5 to about 50% by weight.
7. The process of Claim 1, wherein said cellulose poly-mer has a molecular weight of above about 1,000.
8. The process of Claim 2, wherein said cellulose polymer has a molecular weight of above about 1,000.
9. The process of Claim 1, wherein said spray drying is conducted at atmospheric pressure and at a temperature of above about 60°C.
10. A composition comprising at least one amorphous solid macrolide antibiotic and a cellulose polymer, which is prepared by a method as defined in any of claims 1, 3 or 7.
11. A composition comprising at least one amorphous solid macrolide antibiotic and a cellulose polymer chosen from the group consisting of ethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose whenever prepared by the process as claimed in claims 2, 4 or 5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4182275A JPS51118816A (en) | 1975-04-08 | 1975-04-08 | A process for stabilizing non-crystalloidal solid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1063936A true CA1063936A (en) | 1979-10-09 |
Family
ID=12618972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA249,607A Expired CA1063936A (en) | 1975-04-08 | 1976-04-05 | Preparation of amorphous solid of macrolide antibiotics |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS51118816A (en) |
| CA (1) | CA1063936A (en) |
| DE (1) | DE2615403C2 (en) |
| ES (1) | ES446801A1 (en) |
| FR (1) | FR2306705A1 (en) |
| GB (1) | GB1534070A (en) |
| MX (1) | MX3401E (en) |
| NL (1) | NL176270C (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5819844B2 (en) * | 1978-07-13 | 1983-04-20 | 三菱自動車工業株式会社 | Engine fuel supply system |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
| JPS56103109A (en) * | 1979-08-31 | 1981-08-18 | Eisai Co Ltd | Ubidecarenone-containing composition having improved dispersion properties |
| FR2525108B1 (en) * | 1982-04-19 | 1989-05-12 | Elan Corp Ltd | HIGH-SOLUBILITY MEDICINES AND PROCESS FOR OBTAINING THEM |
| US4767789A (en) * | 1986-10-21 | 1988-08-30 | American Home Products Corporation (Del.) | Spray dried acetaminophen |
| GB9713730D0 (en) * | 1997-06-30 | 1997-09-03 | Ciba Geigy Ag | Organic compounds |
| US6350786B1 (en) * | 1998-09-22 | 2002-02-26 | Hoffmann-La Roche Inc. | Stable complexes of poorly soluble compounds in ionic polymers |
-
1975
- 1975-04-08 JP JP4182275A patent/JPS51118816A/en active Granted
-
1976
- 1976-04-05 CA CA249,607A patent/CA1063936A/en not_active Expired
- 1976-04-07 NL NL7603635A patent/NL176270C/en not_active IP Right Cessation
- 1976-04-08 MX MX15676U patent/MX3401E/en unknown
- 1976-04-08 DE DE19762615403 patent/DE2615403C2/en not_active Expired
- 1976-04-08 GB GB1423476A patent/GB1534070A/en not_active Expired
- 1976-04-08 ES ES446801A patent/ES446801A1/en not_active Expired
- 1976-04-08 FR FR7610280A patent/FR2306705A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| GB1534070A (en) | 1978-11-29 |
| DE2615403A1 (en) | 1976-10-28 |
| DE2615403C2 (en) | 1982-07-15 |
| NL176270B (en) | 1984-10-16 |
| JPS5545042B2 (en) | 1980-11-15 |
| NL176270C (en) | 1985-03-18 |
| ES446801A1 (en) | 1977-06-01 |
| NL7603635A (en) | 1976-10-12 |
| MX3401E (en) | 1980-10-30 |
| JPS51118816A (en) | 1976-10-19 |
| FR2306705A1 (en) | 1976-11-05 |
| FR2306705B1 (en) | 1980-07-18 |
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