GELATTN coMsosirioN FOR CAPSULES No Drawing. Application April 27, Serial No. 580,997
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6 Claims. (Cl. 167-=83) This invention relates to improved plasticized gelatin compositions for capsules and more particularly to gelatin capsules capable of retaining deliquescen-t or hygroscopic chemicals which are deleterious to gelatin. Difiiculty has been encountered in capsulating chemicals such as liquid non-ionic detergents, salts of strong acids and bases, choline chloride, chloral hydrate and similar materials. These materials tend to attack the gelatin shell and cause it to disintegrate, even when dispersed in oily vehicles, apparently due to the presence of moisture in the gelatin. With so-called standard gelatin capsule compositions it is not possible to reduce the moisture to a. safe level from the disintegration standpoint, and at the same time be able to form the capsules on continuous capsulating equipment. Standard gelatin compositions are well known and contain, for example, equal parts of water and gelatin andfrom -50% plasticizer on the absolute basis. The hardness of the finished capsules may range from hard to soft in proportion to the plasticizer content. The gelatin from which these standard compositions are prepared normally has a viscosity of from 34-46 millipoises and a Bloom strength of from 135-165 grams. The gelatin is usually made from alkalitreated bone precursor in accordance with the conventional liming process. Such gelatin, having a viscosity of 34 millipoises or above, requires a relatively large proportion of water to render it sufficiently flexible to permit casting the gelatin into sheets and molding capsules from the sheets. As indicated, the presence of such quantities of water apparently promotes a reaction with the hygroscopic chemical content which brings about disintegration of the capsules. The rate of disintegration varies with the nature of the material being capsulated. In some cases the action is so severe that the capsule cannot be formed, but disintegrates during formation. In other cases the disintegration occurs more slowly with the capsule becoming soft and tacky shortly after formation, and finally collapsing. It is suspected that destruction of the capsule is caused by hydrolysis of the wall thereof, although we are not certain as to the exact mechanism of the break down.
Thus, it is the primary object of this invention to provide a gelatin composition for capsules which will not disintegrate in contact with hygroscopic chemicals of the type described and which lends itself to the manufacture of capsules on continuous capsule forming machines.
We have discovered that gelatin capsules having a surprising resistance to hygroscopic chemicals or chemicals that have a hydrolytic effect on standard gelatin compositions can be made from compositions comprising plasticizer, water and a specially-selected low viscosity, high Bloom strength gelatin (as compared with standard viscosity, standard Bloom strength gelatins described above) prepared from acid-treated bone precursor. More specifically, capsule shell compositions capable of with.- standing deterioration by solutions or dispersions of hygroscopic chemicals have been prepared from such gela- 2,870,062 Patented Jan.,20, .
tin having a viscosity within the range of 15 to 30 millie poises, and a Bloom strength of above 125 grams. Preferably, the gelatins suitable for use in our invention have a viscosity of from 24 to 28 millipoises and a Bloom strength of about 250 grams. Gelatins having a viscosity over 30 millipoises require quantities of water which reduce the resistance of the shell to hygroscopic chemicals. Gelatins having a viscosity below 15 are practically glues and are too weak for the preparation of capsules that will be subject to handling. Gelatins of this kind may be compounded with a minimum water content, and surprisingly, provide remarkable resistance to chemicals that attack standard gelatin even in the presence of quantities of moisture that cause disintegration of standard gelatin.
The viscosity figures set out in this specification were all measured on a 6%% aqueous solution of gelatin as received (the gelatin as received usually contains a small amount of moisture). The pipette method, which is standard in the industry for measuring viscosity, was used in determining gelatin viscosities set forth herein. The gelatin solution is immersed in a water bath maintained at 60 C.:0.2 C. to bring the solution to this temperature. The time in seconds for cc. of solution to pass through the capillary of the pipette is determined. This figure is inserted in a proper formula obtained by calibrating the pipette to give the viscosity in millipoises.
The Bloom strength is a designation of gel strength and is determined by measuring the weight in grams required to depress a cylindrical foot 12.7 millimeters in diameter to a depth of 4 millimeters in a 6%% aqueous solution of gelatin which has been previously chilled for 18 hours at 10 C. This method of determining gel strength is standard in the glue and gelatin industries and is described in detail in Ofiicial Methods of Analysis of the Associa-. tion of Official Agricultural Chemists, seventh edition, page 339 (). The apparatus upon which the test is run is known as a Bloom Gelometer.
A representative commercially available gelatin for use in preparing compositions in accordance with this invention is made from bone precursor processed with acid instead of the usual alkali. The process also includes the step of demineralization by contacting the gelatin solution with an ion exchange resin. Such a gelatin should meet the following specifications:
Bloom strength- Greater than 225 grams.
Viscosity 26 plus or minus 2 millipoises.
Moisture content 12 plus or minus 2%.
pH 5 plus or minus 0.3.
Sulfur dioxide.-- Less than 60 parts per million.
Peroxide Less than 60 parts per million.
Heavy metals Must meet U. S. P. requirements.
Iron Less than 16 parts per million.
Ash 1 Not more than 0.7%.
Mesh size Not more than 5% passing 60 mesh screen.
1 This ash content is very low as compared with that found in standard gelatin.
The preferred gelatin used in the present invention is unusual in that it has an extremely high Bloom strength water may be capsulated in lesser quantities since decomposition caused by hydrolysis is minimized. Where high moisture content is present in the gelatin shell, ingredients whose stability is affected by moisture must be used in quantities in excess of the dosage required because of the deterioration which takes place upon standing.
Another advantage of the present invention lies in the fact that special drying techniques for the capsules may be eliminated, thus saving production time. With standard gelatin the Water must be removed from the shell as quickly as possible after capsule formation. to prevent deterioration.
The particular plasticizer employed in the compositions of the invention is not critical. Any gelatin plasticizer commonly used in the art is satisfactory, for example, edible polyhydric alcohols such. as glycerin, propylene glycol and sorbitol. The plasticizer content determines the resiliency of the finished gelatin capsule and may vary within the range of from 15 to 50% of the total weight of the composition.
In preparing the gelatin compositions, the special low viscosity, high Bloom gelatin is blended with the plasticizer in a suitable mixer to form a plaste. The mixer may be of the Hobart type, the pony type, or any other suitable apparatus adapted to mix powders and liquids to form pasty or viscous masses. to the gelatin-plasticizer paste and mixing is continued until a homogeneous fluffy mass is formed. The ratio of water to gelatin by weight may range from 0.6 to 0.85, preferably from 0.7 to 0.74. Generally the lower the water content, the better the finished capsule resists deter'ioration, but a minimum amount of water is required to provide a flexible gelatin composition that processes readily on the capsulating apparatus. Although the high Bloom gelatin can be processed using less water, it has the unusual property of withstanding deterioration by the chemical content even at water contents higher than the minimum required for processing. Thus, it lends itself Well to commercial production.
The percentage of plasticizer is not critical and may vary widely depending upon the hardness desired in the final capsule. However, 15 to 50% plasticizer based upon the total weight of the constituents is a satisfactory range for purposes of this invention. The homogeneous mixture of the three ingredients is transferred from the mixing receptacle to a melter where it is subjected to heat and vacuum until a smooth, fluid, air-free mass is obtained.
Examples of formulations illustrating the invention are set forth in the table below. These formulas are mixed in accordance with the instructions given above. It should be pointed out that the percentages set out for each ingredient are absolute, i. e. the water content is the total amount present including that inherently present in the gelatin (usually about 11%) and in the glycerin (usually about 5%) as well as the amount added as such.
Water is then added Percent by weight absolute Hardness Example Finished Capsule Gelatin Glycerin Water K 47. 6 1S. 1 3 1. 3 hard. 45. O 22. 5 32. 5 medium hard. 13. 1 25. 8 31.1 medium.
Gelatin derived from acid-treated bone precusor, having a viscosity of 26 millipoises and a Bloom strength of 230 grams, was used in the examples above. The gelatin conformed to the detailed specification set forth above.
The above gelatin formulations were formed into chloral hydrate capsules in accordance with the procedure outline below. The capsules were filled with 7.5 minims of chloral hydrate in olive oil (dosage of chloral hydrate equals 0.25 gram). In each case the gel mass processed Well and made up into tightly sealed, high strength capsules which remained in good condition after storage. The percentage of defective capsules during manufacture was exceptionally low, being less than ten in a run of more than five thousand. Chloral hydrate is used as an example since it is probably one of the most diificult hygroscopic materials to capsulate.
Capsules of these compositions may be simultaneously formed and filled using a method and apparatus such as that disclosed in Scherer United States Patents Nos. 1,970,395, 2,288,327 and 2,318,718. The gelatin composition is first cast into endless ribbons about .030 inch to .070 inch thick on drums comprising part of the capsulating machine. A pair of such ribbons is advanced continuously along a converging path into juxtaposition between a pair of die rolls, each roll having a plurality of cooperating die cavities adapted to form a spherical shell from the gelatin ribbons about an accurately measured dosage of liquid content which is discharged into the space between the ribbons. Of course, the capsule need not be spherical in shape but may be cylindrical with rounded ends, or ellipsoidal, or any other appropriate rounded shape. The pressureof the delivery of the fluid dosage deforms preselected areas of the ribbons into conformation with the cavities of the dies and the dies apply the pressure required to seal the gelatin at the periphery of the capsule. This capsulating operation is performed without trapping any air within the capsule and without wasting any of the fluid content.
After forming, the capsules may be immersed in acetone, to pro-extract moisture, and then dried by irradiation, while constantly agitating, or in an oven maintained at about F. Such treatment is not necessary, however, and is used only with the most destructive of hygroscopic chemicals.
The gelatin compositions of this invention may be processed on apparatus of this type without changing the equipment or the process in any substantial manner. The gelatin film employed is pliable upon entering the dies and can bereadily shaped and sealed in the usual manner.
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.Hygroscopic materials to be capsulated in the compw sitions of this invention are conventionally prepared in solution form. For example, in making chloral hydrate capsules, U. S. P. chloral hydrate, which contains about 99.5% CCl CH(0H) and which may or may not contain a small amount of moisture, is dissolved in an inert oil solvent or other suitable vehicle. The inert solvent must be liquid at room temperature. Suitable vehicles include water-insoluble vegetable oils like peanut, sesame, cottonseed, olive, corn, or a mineral oil, polyethylene glycols, and fatty acid esters of polyethylene glycols. The solution may contain from 50 to 60% of vehicle and, correspondingly, from 50 to 40% chloral hydrate by weight.
The dosage may be varied by regulating the concentration of the chloral hydrate solution and the size of the capsule. Usually capsules range in content from 5 to 10 minims. With the more concentrated solution it is possible to administer the same dosage of chloral hydrate in smaller capsules which is, of course, a decided advantage.
Examples of materials other than those mentioned above which are moisture sensitive or hygroscopic and which may advantageously be capsulated in accordance with this invention are betaine anhydrous, betaine hydrochloride, vitamin and mineral suspensions in water soluble or dispensible vehicles, penicillin, Aerosol OT and certain low molecular weight alcohols and esters.
This application is a continuation-in-part of our copending application Serial No. 344,898, filed March 26, , now abandoned.
What We claim as new and desire to secure by Letters Patent of the United States is:
1. A composition for encapsulating hygroscopic chemicals comprising gelatin, plasticizer and water, the ratio.
of water to gelatin ranging from 0.70 to 0.74, said gelatin being prepared from acid-treated 'bone precursor and having a viscosity of 15 to 30 millipoises and a Bloom strength in excess of 125 grams. 2. The composition of claim 1 wherein said gelatin has a viscosity of 24 to 28 millipoises and a Bloom strength of about 250 grams.
3. The composition of claim 2 wherein the plasticizer is glycerin.
4. A gelatin capsule comprising a hygroscopic chernical dissolved in an inert vehicle and enclosed in a plasticized gelatin shell, said gelatin being prepared from acid-treated bone precursor and having a viscosity of to 30 millipoises and a Bloom strength in excess of grams.
5. A gelatin capsule in accordance with claim 4 wherein the gelatin is plasticized with glycerin.
References Cited in the file of this patent UNITED STATES PATENTS White Apr. 19, Meyer Feb. 19, OTHER REFERENCES U. S. Dispensatory, 24th ed. (), pp. 494-497.
Organoleptic properties are the physical properties of a substance which can be seen by unaided eyes, so these properties become the first evaluation of a substance. Gelatin occurs from a light amber to a faintly yellow-colored, vitreous, and brittle solid. It is practically odorless and tasteless and is available as translucent sheets, flakes, and granules, or as coarse powder [ 27 ]. The goatskin gelatin obtained was yellowish white in the form of coarse powder, and the powder size was less uniform ( Figure 1 ). The goatskin gelatin was yellower than porcine gelatin (Sigma, St. Louis, MO, USA) but whiter compared to bovine gelatin (Sigma, St. Louis, MO, USA).
The yield of extracted goatskin gelatin was 12.74% ± 0.87 (wet weight basis). The yield of goatskin gelatin in this study was greater than that of Zilhadia et al., (10.26% ± 1.07)< 0.05. The yield increased when the hydrochloric acid concentration was raised to 4%. A higher yield indicates enough time to process the bond breaking in collagen. The ionic strength of the solution at an acidic pH facilitates the swelling process caused by the repulsion on the structure of collagen. With the loss of bonding power, warm water will be able to penetrate effectively into the matrix [ 5 26 ].
The clarity value of goatskin gelatin is low. It can be caused by inorganic contaminants, proteins, and mucosal compounds which are inseparable during extraction. Inorganic contaminants can be insoluble particles that spread light and particles that cause turbidity in the solution. In addition, the value of clarity is strongly influenced by the filtration process [ 8 ]. Although the gelatin transmittance is 56.9%, it physically looks like a clear solution, making it possible to be used in the production of hard-shell capsules.
The clarity of gelatin solution (in water) is an important indicator to be applied in the drug, food, and cosmetic fields. It is directly related to its aesthetic value and the color produced. Gelatin color is influenced by the extraction methods and raw materials used [ 28 ]. In this study, the clarity determination was carried out by comparing water transmittance (the value of water transmittance is 100) with the gelatin solution transmittance as measured by a spectrophotometry. The transmittance value of the gelatin obtained was 56.9% ± 0.95.
Gelatin that meets the requirement has a pH of 3.8&#;5.5 [ 4 ]. A pH has an effect on the properties of gelatin as an excipient ingredient. The pH of gelatin is related to the process or treatment. A pH of 5 gives an ideal effect on the gel strength [ 8 ]. In this study, the pH of goatskin gelatin was 5.11 ± 0.09, indicating that it has fulfilled the requirement.
The presence of protein at very high levels and ash, lipid, and moisture of goatskin gelatin at very low levels shows that the goatskin gelatin meets the requirements [ 31 ].
Fat content is one parameter that indicates the purity of gelatin. The lower the fat content, the purer the gelatin produced [ 31 ]. In this study, the fat content of the goatskin gelatin was 2.08% ± 0.35. According to the requirement, the fat content should be <5% [ 2 ].
Ash content is one of the requirements that must be fulfilled by gelatin. Low ash levels indicate good quality gelatin [ 30 31 ]. The requirement for gelatin ash levels is not more than 2&#;2.5% [ 27 32 ]. The ash content of the goatskin gelatin obtained was 0.18% ± 0.07.
Moisture content becomes the test required for gelatin. Water in a substance is one of the factors that influence metabolic activities, such as enzyme activity, microbial activity, and chemical activity. Meanwhile, water in gelatin determines stability, acceptability, freshness, texture, taste, and durability of food and drugs. In addition, dry gelatin is stable in the air. The moisture content of gelatin is between 8&#;13% [ 4 ], and the moisture content of the goatskin gelatin in this study was 9.23% ± 0.08.
The proximate compositions of goatskin gelatin consist of protein, moisture, ash, and fat contents. The main content of gelatin is protein [ 29 31 ]. High levels of protein indicate good quality gelatin. The protein content in the goatskin gelatin was 97.51% ± 1.1, which shows that the main component of the composition of goatskin gelatin is protein.
Gel strength is one of the most important functional properties of gelatin [ 8 31 ]. The gel strength of the goatskin gelatin obtained was 298 ± 2.64 gbloom. Gel strength is categorized into three groups of low bloom (<150 gbloom), moderate bloom (150&#;220 gbloom), and high bloom (220&#;300 gbloom) [ 29 ]. Based on this category, the gel strength of the goatskin gelatin is classified as high gel strength. For the manufacture of capsule shells, the strength of good gelatin is 240&#;300 gbloom [ 4 ]. Therefore, based on the gel strength, the goatskin gelatin is suitable for the production of hard-shell capsules.
Viscosity is an important characteristic of gelatin included at the time of capsule shell making for both hard-shell capsules and soft capsules [ 4 33 ]. The viscosity of gelatin solution has a direct effect when a mold pin is dipped, lifted, and dried. If the viscosity of gelatin solution is not suitable, thick capsules with ununiform weight and size are produced. The viscosity of the goatskin gelatin was 27.33 ± 2.07 mPs. According to GMIA, the viscosity of capsule shells is 25&#;55 mPs [ 4 ]. Therefore, the viscosity of the goatskin gelatin solution can be used to prepare capsule shells.
According to the United States Pharmacopeia 34 and National Formulary, pharmaceutical gelatin should not containand 34 ]. On the other hand, gelatin is stable in the air when it is dry but subject to microbial decomposition when it becomes moist [ 23 ]. Therefore, microbial assay is crucial in gelatin characterization. The results of microbial assay show that the gelatin does not contain Salmonella species and. There is no microbial growth because the final production stage is heating. After gelatin is produced, it is stored in airtight containers to protect it from the influence of air humidity.
The minor components (less than 2%) of the goat skin gelatin extracted were isoleucine (1.40%), methionine (1.15%), tyrosine (1.11%), histidine (1.03%), and cystine (0.01%). Cystine and tryptophan are not commonly present in gelatin. However, cystine was detected in this study. Sarbon et al. () report that cystine is detected at 0.16% in gelatin derived from chicken skin and at 0.47% in bovine skin gelatin [ 29 ]. Cystine is detected due to the presence of a few hairs left during the unhairing process [ 5 ].
The major amino acid composition of goatskin gelatin is glycine (29.13%), followed by proline (13.38%), arginine (10.03%), glutamic acid (9.60%), and alanine (8.43%). The major composition of bovine gelatin is glycine (31.15%), glutamic acid (12.31%), arginine (9.64%) alanine (9.62%), and proline (8.57%). Meanwhile, the content of porcine gelatin is glycine (28.24%), proline (14.12%), glutamic acid (11,52%), arginine (9.40%), and alanine (9.02). Based on the glycine and proline content as the major gelatin components, the goatskin gelatin seemed to be similar to porcine gelatin and differed from bovine skin gelatin. The five main amino acids in goatskin in this study were the same as the amino acids in the goatskin gelatin produced through the alkaline hydrolysis method conducted by Mad-Ali et al., , which include glycine, proline, alanine, glutamic acid, and arginine [ 5 14 ].
The functional properties of gelatin are influenced by the amino acid composition of gelatin constituents. The amino acid composition of gelatin from goat skin, bovine skin, and porcine skin are shown in Table 1
Microscopic structure of goatskin gelatin compared to bovine gelatin and porcine gelatin can be seen in Figure 2
Bovine gelatin has an irregular, asymmetrical shape, but the particles look more uniform with a length between 359 μm and 488 Bovine gelatin has an irregular, asymmetrical shape, but the particles look more uniform with a length between 359 μm and 488 μm. The surface has pores and looks rougher. Porcine gelatin has an irregular, asymmetrical shape and a non-uniform size with a particle length between 248 μm and 445 μm. The surface is non-porous, and among the three gelatin types, pork gelatin has the smallest particles. Meanwhile, goatskin gelatin is flat, with an extremely variable size ranging from 444 μm to 986 μm. The surface is smooth, non-porous, but irregular in shape.
The surface morphology of goatskin gelatin is different from that of bovine gelatin and porcine gelatin. Bovine and porcine gelatin have a round and more regular shape while goatskin gelatin is flat and less uniform. This is due to differences in the refining process. The gelatin industry reduces the size of gelatin using machines. Meanwhile, the goatskin gelatin in this study was refined using a blender. Blender blades produce non-uniform shapes. The surface has pores and looks rougher. Porcine gelatin has an irregular, asymmetrical shape and a non-uniform size with a particle length between 248 μm and 445 μm. The surface is non-porous, and among the three gelatin types, pork gelatin has the smallest particles. Meanwhile, goatskin gelatin is flat, with an extremely variable size ranging from 444 μm to 986 μm. The surface is smooth, non-porous, but irregular in shape.
The surface morphology of goatskin gelatin is different from that of bovine gelatin and porcine gelatin. Bovine and porcine gelatin have a round and more regular shape while goatskin gelatin is flat and less uniform. This is due to differences in the refining process. The gelatin industry reduces the size of gelatin using machines. Meanwhile, the goatskin gelatin in this study was refined using a blender. Blender blades produce non-uniform shapes.
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