CA1270759A - Soft gelatin capsules and process for manufacture - Google Patents
Soft gelatin capsules and process for manufactureInfo
- Publication number
- CA1270759A CA1270759A CA000502104A CA502104A CA1270759A CA 1270759 A CA1270759 A CA 1270759A CA 000502104 A CA000502104 A CA 000502104A CA 502104 A CA502104 A CA 502104A CA 1270759 A CA1270759 A CA 1270759A
- Authority
- CA
- Canada
- Prior art keywords
- capsules
- soft gelatin
- gelatin capsules
- polyethylene glycol
- solvent
- 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 - Fee Related
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- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Soft gelatin capsules with a gelatin shell, at least one plasticizer and a capsule filling that contains at least one pharmacologically-active substance and a solvent containing at least 50% by weight of a mixture of polyethylene glycol ethers of tetrahydrofurfuryl alcohol having the formula I:
Soft gelatin capsules with a gelatin shell, at least one plasticizer and a capsule filling that contains at least one pharmacologically-active substance and a solvent containing at least 50% by weight of a mixture of polyethylene glycol ethers of tetrahydrofurfuryl alcohol having the formula I:
Description
~ ~'7~ 59 BACKGROUND OF THE INVENTION
Field of the Invention The present invention concerns soft gelatin capsules with a gelatin shell, at least one plasticizer, and a capsule filling which contains at least one pharmacologically-active substance and a solvent, as well as processes for their manufacture.
Description of the Prior Art Gelatin capsules, especially soft gelatin capsules, have become increasingly important as a form of medication since it became feasible, in the 1930's, to manufacture them by making and filling the capsules in one operation. Compared to other dosage forms, they show a number of advantages.
Thus, they are odorless and tasteless, they can be taken easily and, owing to their swelling capability~ and water solubility, the drugs are readily liberated in the stomach. Numerous drugs which, on account of their sensitivity to oxidation and to light, their thermal stability or their hygroscopicity, may not be processed into other medicinal ~orms, can be encapsulated without impairment of their function.
Soft gelatin capsules serve chiefly for the containment of liquids, i.e. oily solutions, suspensions or emulsions. Vegetable , animal and mineral oils, liquid hydrocarbons, ethereal oils and also polyethylene glycols are in use as fillings. Fats and waxes are also applied or admixed to increase the consistency.
Polyethylene glycols are superior to other possible filling materials for 50ft gelatin 127~3~75~
capsules in a number of ways. In contrast to oily liquids, polyethylene glycols are mixable with water in all proportions.
At the same time, because polyethylene 5 glycols are able to dissolve many drugs which are sparingly soluble or insoluble in water, the use of polyethylene glycols, with such drugs, makes possible a particularly favorable liberation of the active material. In many cases, sparingly water 10 soluble drugs, which have been dissolved in polyethylene glycols and then put into soft ~elatin capsules, are outstanding, by virtue of an exceptionally good bio-availability of the drug.
From DE-OS 33 07 353 of the applicant, 15 soft gelatin capsules are known in which the dried capsule shell contains 4 to 40% by weight of sorbitol and/or sorbitan, the polyethylene glycol used in the capsule filling for solution and suspension of the active material is at least 50~
20 by weight of a polyethylene glycol having a mean molecular weight of 600, and the capsule filling contains up to 20~ by weight of glycerol and/or propylene glycol. These soft gelatin capsules have been remarkably successful, yet they still have the 25 disadvantage that a number of active material~ are not sufficiently soluble in polyethylene glycol.
Consequently, large capsules are necessary for the encapsulation of such sparingly soluble active materials. There exists, therefore, a continuing 30 need for solvents which are able to dissolve larger amounts of acti~-e materials and yat can be processed into stable soft gelatin capsules.
Solvents, suitable for human consumption, such as ethanol, propylene glycol, dimethyl acetamide~
35 lactic acid, glycerol, butanediol, and the ~ ~'7~
polyethylene glycol ethter of tetrahhydrofurfuryl alcohol, have been shown by the invastigations of the applicant to be unsuitable for introduction into soft gelatin capsules in larger quantities, because the capsule fillings made with these solvents cause, after a short time, softening and deformation of the capsules produced, which therefore are not marketable.
The reasons for these stability problems are evidetly to be sought in the good water miscibility and the lower molecular weight of these solvents.
~'7~5~
SUMMARY OF THE INVENTION
Surprisingl~, it has now been found that mixtures of polyethylene glycol ethers of tetrahydrofurfurol are suitable solvents for active materials in soft gelatin capsules, if the capsule filling is encapsulated in a wet gelatin shell and the capsules obtained are intensively dried for at least 5 days, and preferably for 6 to 10 days.
After 5 to 10 days, the quantities of water which pass from tha wet gelatin shell into the capsule filling during encapsulation have obviously been removed to such an extent that they, together with the polyethylene glycol ethers of tetrahydro~urfuryl alcohol, are no longer able, subsequently, to soften the gelatin shell again and enable the low molecular weight solvents to escape.
Such a long and intensive drying of soft gelatin capsules is decidedly unusual; commonly they are dried for only 1 to 4 days. Longer drying times not only cause unnecessary costs, but also lead to an undesirable hardening and embrittlement of the capsule shell. In the inventive process, certain amounts of the polyethylene glycol ethers of tetrahydofurfurol apparently migrate into the capsule shell and function there as a sotener, counteracting the hardening and embrittlement of the capsule shell otherwise observed on drying for too long. These quantities of the polyethylene glycol ethers of tetrahydrofurfurol, functioning as a softener in the capsule shell, also lead, however, to increased sensitivity of the inventive capsules to atmospheric moisture, so the finished capsules should be stored out of contact with atmospheric moisture. However, capsules ~L27~ 59 manufactured according to the invention and stored with atmospheric moisturs excluded have been found to be still completely stable after 3 years.
For the first time, therefore, the manufacture of stable soft gelatin capsules with a low molecular weight organic solvent, mixable with water in all.proportions, has been successful and a wide field of possible new applications for this solvent has been opened up.
DETAILED DESCRIPTION OF ~HE INVENTION
The polyethylene glycol ethers of tetrahydrofurfurol have the general formula I:
CE~2 - CH2 CH2 ~C CH2(OCH2 ,CH2)nOH
where n = 1 to 6.
In particular, mixtures in which n = 1 to 6 or in which n = 1 and 2 are commercially available and suitable for human consumption. Thus, the commercial products "Glyco~urol 75" (a mixture of mono- and di-ethylene glycol ethers in a ratio of approximately 1 : 1, wikh a mean molecular weight of about 168) and Tetra~lykol ~ (a mixture of mono-ethylene glycol ether, di-ethylene glycol ether and variable proportions of tri-, tetra- and penta-ethylene glycol ethers, with a mean molecular weight of about 190) are especially suitable~ A
number of sparingly soluble active materials are substantially more soluble in these sol~ents than in polyethylene glycol, so that soft gelatin capsules, according to the invention which axe lX70t7~9 substantially smaller and more pleasant to take, may be manufactured. For example, the ~wo interesting active materials, diazepam and nifedipine, are practically twice as soluble in the solvent used according to the invention as in Polyethylenglycol 400.
In addition, it has been found that not only pure mixtures of polyethylene glycol ethers of tetrahydrofurfuryl alcohol are suitable, but also mixtures with other customary solvents and solvent aids. In particular, up to 50% by weight of lQ polyethylene glycol, with a molecular weight of 30Q to 600 can be added to the polyethylene glycol ethers of tetrahydrofurfuryl alcohol ! without changing its solubility for sparingly soluble active materials ~oo much.
The invention therefore relates to soft gelatin capsules with a gelatin shell, at least one plasticizer and a capsule filling that contains at least one pharmacologically active substance and a solvent, the solvent containing at least 50% by weight of a mlxture of polyethylene glycol ethers o~
tetrahydrofurfuryl alcohol of the formula I as defined above.
Solvent aids and emulsifiers, which are themselves soluble, can be added to increase the solubility of certain active materials in the solvents and solvent mixtures used according to the invention.
The customary plasticizers, suah as glycerol, sorbitol, sorbitan etc. are added to the;gelatln shell.
~2'7~)'759 6a 61368-773 In addition, other customary auxiliary agents, such as a preservative (e.g. p-aminobenzoic acid and potassium sorbate), dyestuffs, pigments, flavorings or perfumes, can be added to the capsule shell. Desirably, the finished capsules can subsequently also be provided with special coatings to facilitate or improve their application. The polyethylene glycol ethers of tetrahydrofurfuryl alcohol, used according to the invention, are pharmacologically and toxicologically unob~ectionable an~ are already established to a .: . -: .
considerable extent for the manufacture ofinjection solutions. In the past, the oral application of active materials in these solvents has not occurred because the polyethylene glycol ethers of tetrahydrofurfuryl alcohol tastes decidedly unpleasant. A further advantage o~ the present invention is, therefore, that these good solvents for many active materials have now also become available for oral dosage forms. The relatively small amounts of the solvents in the capsule shell do not in any way impair the oral application of the inventive soft gelatin capsules.
The inventive soft gelatin capsules and the process for their manufacture are explained in more detail in the following examples and comparative tests.
S00 mg of the commercial product Tetraglykol ~ was first, without ad~ition of active materials or auxiliary agents, introduced into soft gelatin capsules which were then dried at 20 degrees C and 20 to 25% relative humidity, some for only 1 day and some for 3, 5, 8 and 10 days.
After a few weeks, the solvent escaped through the capsule shell from those capsules that were dried for only 1 day, so that these capsules were useless as a commercial product. The capsules that were dried for 3 days were stable for only 12 months.
The capsules that had been dried according to the invention for 5, 8 or 10 days were, under the same storage conditions, completely stable for 3 years.
Also, with 8 and 10 days drying, no embrittlement took place.
~L2~70~759 Comparative solubility investigations of the active materials nifedipine and diazepam in polyethylenglycol 400 and Tetraglycol R yielded the following values, in % by weight, for the maximum solubility at 21 degrees C:
Active material Diazepam Nifedipine PEG 400 5.9~ 4O9%
Tetraglyco~ 11.5% 10.2%
The following recipes were prepared, corresponding to the usual dosages o~ ni~edipine and dia2epam.
The data refer to mg/capsule.
1. Nifedipine 10.0 mg Tetraglykol~ 110.0 m~
120.0 mg 20 2. Diazepam 5.0 mg Tetraglykol 115.0 mg 120.0 mg 3. Diazepam ~ 5.0 mg Tetraglykol 60.0 mg PEG 400 50.0 mg Glycerol 5.0 mg 120.0 mg These solutions of active materials were formed into oval capsules within the very small, and therefore readily swallowed, capsule size of 2 minims and dried for 6 days in each case. On storage, in the absence o~ atmospheric moisture, ~27(~7~9 g_ the capsules were completely stable, like the capsules without the active material.
Field of the Invention The present invention concerns soft gelatin capsules with a gelatin shell, at least one plasticizer, and a capsule filling which contains at least one pharmacologically-active substance and a solvent, as well as processes for their manufacture.
Description of the Prior Art Gelatin capsules, especially soft gelatin capsules, have become increasingly important as a form of medication since it became feasible, in the 1930's, to manufacture them by making and filling the capsules in one operation. Compared to other dosage forms, they show a number of advantages.
Thus, they are odorless and tasteless, they can be taken easily and, owing to their swelling capability~ and water solubility, the drugs are readily liberated in the stomach. Numerous drugs which, on account of their sensitivity to oxidation and to light, their thermal stability or their hygroscopicity, may not be processed into other medicinal ~orms, can be encapsulated without impairment of their function.
Soft gelatin capsules serve chiefly for the containment of liquids, i.e. oily solutions, suspensions or emulsions. Vegetable , animal and mineral oils, liquid hydrocarbons, ethereal oils and also polyethylene glycols are in use as fillings. Fats and waxes are also applied or admixed to increase the consistency.
Polyethylene glycols are superior to other possible filling materials for 50ft gelatin 127~3~75~
capsules in a number of ways. In contrast to oily liquids, polyethylene glycols are mixable with water in all proportions.
At the same time, because polyethylene 5 glycols are able to dissolve many drugs which are sparingly soluble or insoluble in water, the use of polyethylene glycols, with such drugs, makes possible a particularly favorable liberation of the active material. In many cases, sparingly water 10 soluble drugs, which have been dissolved in polyethylene glycols and then put into soft ~elatin capsules, are outstanding, by virtue of an exceptionally good bio-availability of the drug.
From DE-OS 33 07 353 of the applicant, 15 soft gelatin capsules are known in which the dried capsule shell contains 4 to 40% by weight of sorbitol and/or sorbitan, the polyethylene glycol used in the capsule filling for solution and suspension of the active material is at least 50~
20 by weight of a polyethylene glycol having a mean molecular weight of 600, and the capsule filling contains up to 20~ by weight of glycerol and/or propylene glycol. These soft gelatin capsules have been remarkably successful, yet they still have the 25 disadvantage that a number of active material~ are not sufficiently soluble in polyethylene glycol.
Consequently, large capsules are necessary for the encapsulation of such sparingly soluble active materials. There exists, therefore, a continuing 30 need for solvents which are able to dissolve larger amounts of acti~-e materials and yat can be processed into stable soft gelatin capsules.
Solvents, suitable for human consumption, such as ethanol, propylene glycol, dimethyl acetamide~
35 lactic acid, glycerol, butanediol, and the ~ ~'7~
polyethylene glycol ethter of tetrahhydrofurfuryl alcohol, have been shown by the invastigations of the applicant to be unsuitable for introduction into soft gelatin capsules in larger quantities, because the capsule fillings made with these solvents cause, after a short time, softening and deformation of the capsules produced, which therefore are not marketable.
The reasons for these stability problems are evidetly to be sought in the good water miscibility and the lower molecular weight of these solvents.
~'7~5~
SUMMARY OF THE INVENTION
Surprisingl~, it has now been found that mixtures of polyethylene glycol ethers of tetrahydrofurfurol are suitable solvents for active materials in soft gelatin capsules, if the capsule filling is encapsulated in a wet gelatin shell and the capsules obtained are intensively dried for at least 5 days, and preferably for 6 to 10 days.
After 5 to 10 days, the quantities of water which pass from tha wet gelatin shell into the capsule filling during encapsulation have obviously been removed to such an extent that they, together with the polyethylene glycol ethers of tetrahydro~urfuryl alcohol, are no longer able, subsequently, to soften the gelatin shell again and enable the low molecular weight solvents to escape.
Such a long and intensive drying of soft gelatin capsules is decidedly unusual; commonly they are dried for only 1 to 4 days. Longer drying times not only cause unnecessary costs, but also lead to an undesirable hardening and embrittlement of the capsule shell. In the inventive process, certain amounts of the polyethylene glycol ethers of tetrahydofurfurol apparently migrate into the capsule shell and function there as a sotener, counteracting the hardening and embrittlement of the capsule shell otherwise observed on drying for too long. These quantities of the polyethylene glycol ethers of tetrahydrofurfurol, functioning as a softener in the capsule shell, also lead, however, to increased sensitivity of the inventive capsules to atmospheric moisture, so the finished capsules should be stored out of contact with atmospheric moisture. However, capsules ~L27~ 59 manufactured according to the invention and stored with atmospheric moisturs excluded have been found to be still completely stable after 3 years.
For the first time, therefore, the manufacture of stable soft gelatin capsules with a low molecular weight organic solvent, mixable with water in all.proportions, has been successful and a wide field of possible new applications for this solvent has been opened up.
DETAILED DESCRIPTION OF ~HE INVENTION
The polyethylene glycol ethers of tetrahydrofurfurol have the general formula I:
CE~2 - CH2 CH2 ~C CH2(OCH2 ,CH2)nOH
where n = 1 to 6.
In particular, mixtures in which n = 1 to 6 or in which n = 1 and 2 are commercially available and suitable for human consumption. Thus, the commercial products "Glyco~urol 75" (a mixture of mono- and di-ethylene glycol ethers in a ratio of approximately 1 : 1, wikh a mean molecular weight of about 168) and Tetra~lykol ~ (a mixture of mono-ethylene glycol ether, di-ethylene glycol ether and variable proportions of tri-, tetra- and penta-ethylene glycol ethers, with a mean molecular weight of about 190) are especially suitable~ A
number of sparingly soluble active materials are substantially more soluble in these sol~ents than in polyethylene glycol, so that soft gelatin capsules, according to the invention which axe lX70t7~9 substantially smaller and more pleasant to take, may be manufactured. For example, the ~wo interesting active materials, diazepam and nifedipine, are practically twice as soluble in the solvent used according to the invention as in Polyethylenglycol 400.
In addition, it has been found that not only pure mixtures of polyethylene glycol ethers of tetrahydrofurfuryl alcohol are suitable, but also mixtures with other customary solvents and solvent aids. In particular, up to 50% by weight of lQ polyethylene glycol, with a molecular weight of 30Q to 600 can be added to the polyethylene glycol ethers of tetrahydrofurfuryl alcohol ! without changing its solubility for sparingly soluble active materials ~oo much.
The invention therefore relates to soft gelatin capsules with a gelatin shell, at least one plasticizer and a capsule filling that contains at least one pharmacologically active substance and a solvent, the solvent containing at least 50% by weight of a mlxture of polyethylene glycol ethers o~
tetrahydrofurfuryl alcohol of the formula I as defined above.
Solvent aids and emulsifiers, which are themselves soluble, can be added to increase the solubility of certain active materials in the solvents and solvent mixtures used according to the invention.
The customary plasticizers, suah as glycerol, sorbitol, sorbitan etc. are added to the;gelatln shell.
~2'7~)'759 6a 61368-773 In addition, other customary auxiliary agents, such as a preservative (e.g. p-aminobenzoic acid and potassium sorbate), dyestuffs, pigments, flavorings or perfumes, can be added to the capsule shell. Desirably, the finished capsules can subsequently also be provided with special coatings to facilitate or improve their application. The polyethylene glycol ethers of tetrahydrofurfuryl alcohol, used according to the invention, are pharmacologically and toxicologically unob~ectionable an~ are already established to a .: . -: .
considerable extent for the manufacture ofinjection solutions. In the past, the oral application of active materials in these solvents has not occurred because the polyethylene glycol ethers of tetrahydrofurfuryl alcohol tastes decidedly unpleasant. A further advantage o~ the present invention is, therefore, that these good solvents for many active materials have now also become available for oral dosage forms. The relatively small amounts of the solvents in the capsule shell do not in any way impair the oral application of the inventive soft gelatin capsules.
The inventive soft gelatin capsules and the process for their manufacture are explained in more detail in the following examples and comparative tests.
S00 mg of the commercial product Tetraglykol ~ was first, without ad~ition of active materials or auxiliary agents, introduced into soft gelatin capsules which were then dried at 20 degrees C and 20 to 25% relative humidity, some for only 1 day and some for 3, 5, 8 and 10 days.
After a few weeks, the solvent escaped through the capsule shell from those capsules that were dried for only 1 day, so that these capsules were useless as a commercial product. The capsules that were dried for 3 days were stable for only 12 months.
The capsules that had been dried according to the invention for 5, 8 or 10 days were, under the same storage conditions, completely stable for 3 years.
Also, with 8 and 10 days drying, no embrittlement took place.
~L2~70~759 Comparative solubility investigations of the active materials nifedipine and diazepam in polyethylenglycol 400 and Tetraglycol R yielded the following values, in % by weight, for the maximum solubility at 21 degrees C:
Active material Diazepam Nifedipine PEG 400 5.9~ 4O9%
Tetraglyco~ 11.5% 10.2%
The following recipes were prepared, corresponding to the usual dosages o~ ni~edipine and dia2epam.
The data refer to mg/capsule.
1. Nifedipine 10.0 mg Tetraglykol~ 110.0 m~
120.0 mg 20 2. Diazepam 5.0 mg Tetraglykol 115.0 mg 120.0 mg 3. Diazepam ~ 5.0 mg Tetraglykol 60.0 mg PEG 400 50.0 mg Glycerol 5.0 mg 120.0 mg These solutions of active materials were formed into oval capsules within the very small, and therefore readily swallowed, capsule size of 2 minims and dried for 6 days in each case. On storage, in the absence o~ atmospheric moisture, ~27(~7~9 g_ the capsules were completely stable, like the capsules without the active material.
Claims (7)
1. Soft gelatin capsules with a gelatin shell, at least one plasticizer and a capsule filling that contains at least one pharmacologically-active substance and a solvent, characterized in that the solvent contains at least 50% by weight of a mixture of polyethylene glycol ethers of tetrahydrofurfuryl alcohol having the formula I:
I, where n = 1 to 6.
I, where n = 1 to 6.
2. Soft gelatin capsules according to claim 1, characterized in that n = 1 and 2.
3. Processes for the manufacture of soft gelatin capsules with a gelatin shell, at least one plasticizer and a capsule filling that contains at least one pharmacologically-active substance and a solvent, characterized in that at least 50% by weight of a mixture of polyethylene glycol ethers of tetrahydrofurfuryl alcohol having the formula I:
I, where n = 1 to 6, is used as the solvent, encapsulated in a wet gelatin shell, and that the capsules obtained are dried for 5 to 10 days.
I, where n = 1 to 6, is used as the solvent, encapsulated in a wet gelatin shell, and that the capsules obtained are dried for 5 to 10 days.
4. Processes according to claim 3 characterized in that n = 1 and 2.
5. Use of mixtures of polyethylene glycol ethers of tetrahydrofurfuryl alcohol having the formula I as defined in claim 1 as solvents for active materials in soft gelatin capsules.
6. Use according to claim 5 characterized in that additional solvents are used.
7. Use according to claim 5 or 6 characterized in that polyethylenglycol is used as an additional solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000502104A CA1270759A (en) | 1986-02-18 | 1986-02-18 | Soft gelatin capsules and process for manufacture |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000502104A CA1270759A (en) | 1986-02-18 | 1986-02-18 | Soft gelatin capsules and process for manufacture |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1270759A true CA1270759A (en) | 1990-06-26 |
Family
ID=4132489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000502104A Expired - Fee Related CA1270759A (en) | 1986-02-18 | 1986-02-18 | Soft gelatin capsules and process for manufacture |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1270759A (en) |
-
1986
- 1986-02-18 CA CA000502104A patent/CA1270759A/en not_active Expired - Fee Related
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