CA1041905A

CA1041905A - Integral solid gel-lattice dosage form of high moisture content

Info

Publication number: CA1041905A
Application number: CA167,309A
Authority: CA
Inventors: John J. Miskel; Warren W. Kindt; Edward C. Connor
Original assignee: Catalent Pharma Solutions Inc
Current assignee: Catalent Pharma Solutions Inc
Priority date: 1972-04-03
Filing date: 1973-03-26
Publication date: 1978-11-07
Also published as: FR2179044A1; JPS5116926B2; JPS499480A; DE2316242A1; FR2179044B1; GB1388786A

Abstract

ABSTRACT OF THE DISCLOSURE
Integral, solid dosage forms containing active chemical compounds in a high moisture content macromolecular gel-lattice vehicle. The gel-lattice matrix vehicle may contain various active chemical compounds in the form of aqueous solutions, aqueous colloidal suspensions, aqueous macro- and microcrystalline suspensions. The gel-lattice matrix vehicle comprises from 4-50% water and sets to a relatively rigid, but not brittle, gel system upon cooling and drying to a final water content of 5-20%, typically 15-20%. The gel-lattice matrix dosageform is sufficiently stable that no capsule covering or shell is required. The gel-lattice dosage forms are extruded or die-formed in various shapes, and do not stick together in bulk. The dosage forms may be used as carriers for various types of chemical compounds, including pharmaceuticals, medicinals, foods, and cosmetics.

Description

Field of the Invention ~ 0~i This invention relates to integral, solid gel-lattice dosage forms compris-ing a special macromolecular gel-lattice matrix vehicle which contains aqueous solutions or suspensions of active chemical compounds such as pharmaceuticals, medicinals, foods, and cosmetics. The dosage form may also be characterized as stable, shell-less "capsules", and are relatively rigid, but not brittle, gels which in their finished state are not surface tacky yet have relatively high moisture content while retaining their elegance over long storage periods.
Because of the ability to accept and retain aqueous solutions and suspensions, the compositions of this invention permit higher active component concentration and faster solution and release in the environment of use.
Background of the Invention This invention is an improvement over the prior art, permitting direct extrusion or injection molding of the total dosage form composition. Typically, two distinct forms of gelatin capsules were well recognized in the art: hard and soft capsules. The hard gelatin capsule type is unplasticized, and is composed of two parts, a cap and a body which are fitted together after the body has been filled with an appropriate component. The soft type is a plasticized capsule of one piece, sealed construction enclosing the components therein. Although both types of capsules are made in various shapes and sizes, and both can enclose a wide variety of components, soft gelatin capsules are used generally for en-closing a fluid or semi-fluid fill, while hard shell, two piece capsules are normally used for powders, or time-delay beadlets.
A well recognized and very serious difficulty in the art of encapsulating components of soft capsules is the inherent and marked affinity of the gelatin capsule shell for water. Special precautions are required to keep the water content in the components and in any accompanying vehicle at a critical mini-mum. Otherwise, the water exerts extremely deleterious effects on the 29 gelatin thus reducing the yield of quality capsules with impaired storage .~a~
stability. Typical defects include leaking, indenting, and shrinking. No less serious are defects of excessively soft capsules or those having soft spots. If special precautions to e~cclude ~vater from the shell and the components are not followed carefully, the soft capsules will break during the encapsulation pro-cess. Even if the capsules do survive this manufacturing process, storage after manufacture results in Eurther softening of the capsules, the appearance of small holes at the point of any contact between water and the gelatin shell of the capsule, the gradual loss of an acceptable character oE the capsules, termed "elegance, " and even loss of the components therein.
The most commonly applied solution to these problems has been the use of a water immiscible oil as the vehicle for the pharmaceutical or chemical component being encapsulated. However, such oily vehicles suffer the disad-vantage of not being readily dispersed in the gastrointestinal tract and the chemical or pharmaceutical components thereof do not go into solution rapidly due to retarding of dissolution by the oil. For instance, after the oral ingestion of gelatin capsules for therapeutic purposes, encapsulated components must normally become dissolved in the aqueous media in the gastrointestinal tract before absorption can take place. The components in oily vehicles for the most part must be leached away from the oil by the aqueous medium before absorp-tion can occur. In addition, the practical manufacture of soft gelatin capsules is greatly hampered by the fact that the components to be encapsulated may be entirely insoluble or only slightly soluble in the oily vehicle which is necessary to protect the outer gelatin shell. As a result, many of the chemical or pharma-ceutical active ingredients are dispersed or suspended rather than carried in solution, and many must be encapsulated in larger capsules than would be necessary if a water-miscible vehicle having no adverse effects on the gelatin were available. In addition, some of the oily vehicles, particularly those carrying suspended components, do not provide uniform suspensions; that is, the amount of the active ingredient per unit of oily vehicle is not always con-stant or easily controllable due to the difficulties of producing uniform sus-pens ions .
Common attempts to solve the above difficulties have not been parti-cularly successful, and result in other drawbacks. These attempts at solu-tions include hardening of the outer shell by modification of the gelatin through use of formaldehyde, a so-called tanning process. Another solution has been to use extremely low amounts of water such as illustrated in U. S. Patent No.
3,445, 563 by drying the beads to a 2% moisture content. However, chemical hardening makes the outer shell difficultly digestible, and drying does not provide for the use of aqueous solutions or suspensions of the active ingredients.
British Patent No. 993, 138 combines both these methods, disclosing "gel-coated" beadlets which are both inherently dry and tanned. Another approach to the problem was proposed in U. S. Patent No. 2, 667,268 which employed, as water inhibitors, hydroxy aliphatic ethers of aliphatic polyols in a preferred proportion of at least 2:1 with reference to water present. Still other solu-tions to the problem involved the use of hygroscopic organic liquids (U. S.
Patent No. 2, 780,355), dioxolane vehicle fills for soft capsules, and water in oil emulsion fills.
All of the above approaches to the problem point to the accepted idea that some relatively expensive, exterior treatment (such as tanning) or encap-sulation is required, and only a non-aqueous, or very low water content (0-2%) vehicle could be used for the chemical compound-containing fill. The opposite concept of a relatively dry, hard dosage form does not provide for fast solution of the carried components in the environment of use, and thus delays effectiveness, particularly in the case of pharmaceuticals.
The aforesaid difficulties in the manufacture, storage, lifetime, effec-tiveness, and use of capsules have caused a long felt but unsolved need for a homogenous vehicle which contains the superior solubilizing and dispersing action of a water-containing medium for use with a wide variety of chemical ` ` : ~ . - - . :

~4~ 5 compounds without the problems and added expense involved in encapsulation.
T~E INVENTION
Objects It is among the objects of this invention to provide a stable, integral gel-lattice dosage form having a water-containing solution or suspension of an active ingredient distributed therein.
It is another object of the invention to provide a method of forming stable, integral gel-lattice dosage forms containing aqueous solutions and sus-pensions of chemical compounds and medicaments therein.
It is another object of this invention to provide an improved composition comprising a homogenous, stable, macromolecular gel-lattice matrix as a carrier for aqueous solutions or suspensions of chemical compounds or medica-ments in the interstices of the matrix structure.
It is another object of this invention to provide a homogenous, macro-molecular gel-lattice containing as high as 15 to 20% water solution of an active ingredient, yet which has a long life and does not exhibit the problems of hydro-scopic softening, deterioration, or attack by substances normally deleterious to capsules.
It is another object of this invention to provide an improved composition 20 which, by virtue of its homogenous, stable composition, can provide a higher concentration of the active ingredient in a smaller volume than heretofore avail-able in capsules.
- It is another object of this invention to provide a shell-less, solid, integral dosage form and a method of manufacture thereof which omits an expen-sive outer encapsulating shell, or special surface treatment.
Still other and further objects of this invention are evident from the detailed description and specific examples which follow.
Summarv and Detailed Description of the Invention We have discovered that a dosage form comprising a homogenous, highly : - .

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stable, non-oleaginous vehicle can be prepared by forming a body structure which consists entirely of a macromolecular gel-lattice matrix structure, here-inafter called a gel-lattice vehicle, ~vhich contains as high as 30 to 50'~0 of an aqueous solution or suspension of a chemical, medicinal, food, or pharmaceu-tical compound in the interstices of the matrix structure. The gel-lattice vehicle may be extruded or injection-molded into conventional configurations.
Upon cooling and drying, the gel-lattice vehicle containing the chemical com-pound sets to a relatively rigid but not brittle gel system containing as much as 15 to Z0% water. No shell or surface treatment is needed for the dosage forms to retain their elegance over long storage periods.
By non-oleaginous, we mean that the vehicle for the solution or suspen-sion of the active ingredient is not the oily or oleaginous type of material here-tofore used. Although we prefer to use only water as the active solvent, we do not intend to exclude from the scope of our invention the use of small percent-ages of non-aqueous, water-miscible solvents for the chemical, medicinal, or pharmaceutical compounds employed as the active ingredient. For example, some chemical or pharmaceutical compounds are preferentially soluble in an aqueous system comprising water and a water-miscible component, such as an alcohol or glycol. These types of systems are also encompassed within the scope of our invention, but in all cases the water content of the oral dosage form is substantially above that heretofore used.
The concentration of the solution or dispersion of the active ingredient is determined by the size of the dose desired. Since the desired volume of the dose is usually predetermined or known, the concentration of the active sub-stance is easily calculable therefrom. Although the ratio of the active ingredi-ent to the solution vehicle may vary over a wide range, a preferred range is from 1:1 to 7 1 by weight. Since the active ingredients are more soluble in water than they are in the conventional oily vehicles, greater concentrations of the active ingredient are possible in the water-containing vehicle-compound Os~
system of this invention. Thus, the compositions of this invention may be of smaller volume ~hich is another decided advantage of the present invention.
The unit dosage forms may be spherical, cylindrical with rounded ends, ellipsoidal or any other appropriate, preferably rounded, shape. The dosage forms are preferably formed by extrusion. Other conventional types of plastic material forming processes and apparatus may be used, such as rotary or reciprocal die forming, or injection molding. The examples given below employed a plastics injection molding device of the "Air Cylinder Honajector"
type. This is a melter-extruder having a ram diameter of from 9/16" to 11/16", a shot capacity of from 9-18 grams maximum, and operates in the temperature range of from 100 to 600F, with a temperature control capable of holding the temperature to i 5F. In production one may use a conventional extrusion unit, similar to that described in U. S. Patent 3, 032, 950, specially equipped with rotary dies to form and cut the dosage form shapes as part of the extrusion operation.
Immediately after formation, compositions of macromolecular gel-lattice matrix containing the aqueous solution or suspension of this invention having from 4-50% water distributed homogenously therethrough, set to a rigid, but not brittle, homogenous gel system upon cooling and/or drying. Dry warm 20 air may be used to help set the gel. The homogenous unit then dries to a point where the moisture level in the macromolecular gel-lattice matrix is relatively uniform and bound in the matrix and is from 5-20% by weight, typically 15-20%.
At this point, the manufacturing process has been completed and the dosage forms are considered to be in final or finished form.
The macromolecular compositions that may be used to form the macro-molecular gel-lattice matrix vehicle for the aqueous solutions or suspensions comprise those macromolecular compounds which are water-soluble or form colloidal hydrates.
Hereafter, in both the specification and the claims, the term "water-' `

soluble macromolecular compounds" should be construed to include those that form colloidal hydrates. Among the water-soluble macromolecular composi-tions that may be used to form the gel-lattice matrices of this invention are polypeptides such as gelatin, casein, collagen, albumin, soya protein and soy peptone; polysaccharides such as pectin, agar, acacia, karaya, tragacanth, Irish moss, algins and alginates, guar. Iceland moss, modified starches; and synthetics such as polyvinyl pyrrolidone, methyl cellulose, sodium carboxy-methyl cellulose, hydroxypropyl cellulose, polyacrylic acid, cross-linked polyacrylic acid and their salts, ethylene maleic anhydride co-polymers and polyvinyl alcohol.
Gel-lattice matrices are prepared as follows: the powdered, flaked, or lump macromolecular polymer is added to water which may be heated and which may contain a plasticizer if required. The mixture is then agitated with low shear agitation to minimize any reduction in the molecular weight of the macro-molecular polymers. The agitator speed is also such as to minimize the incor-poration of air. Any air which is incorporated must be removed during the extrusion operation.
A plasticizer may be incorporated in the formulation to enhance flow properties, or to ensure the macromolecular matrix does not become brittle or lack elasticity on drying. For instance, glycerin is employed in plasticizinggelatin, casein, pectin, alginates, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol and modified starches. Plasticizers such as diethylphthalate, diethyl sebacate, triethyl citrate, may be employed to plasticize methyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone and poly-acrylic acid.
An alternative procedure is as follows: the polymer is weighed into a change-can type mixer. Any plasticizer required is added and the mixture is agitated gently until all particles are uniformly wetted. The agitation is con-tinued and chilled water is added. The agitation or stirring is continued until the polymer ceases to absorb water. The high molecular weight polymer completely absorbs the added water, and a fluffy, soft and slightly agglomer-ated granular gel mass results. This mass is then deaerated during extrusion, at which time the granules melt. In the alternative to extruding the gel gran-ules, a premelted gel can be extruded with concomitant cooling.
We prefer a high concentration of macromolecular gel-lattice matrix having a low viscosity with temperatures as low as possible ;n order to avoid problems during the extrusion and drying operations. However, the viscosity of the gel-lattice matrix is critical only in the sense that it determines the temperature and pressure necessary in forming the unit dosage forms. The viscosity of the melt during extrusion generally ranges from 6, 200 C. P. S. to 254, 000 C. P. S. The dosage form can be fabricated with extrusion type machines, for example as shown in U. S. Patent 3, 032, 950. Conventional injection mold-ing equipment may also be employed. The extrusion or injection molding may utilize either the gel granules or a preformed melt.
In formulations in which we employ gelatin as the gel-lattice matrix, we use a low bloom (low molecular weight) gelatin, preferably ranging from 0 to 40 bloom in order to incorporate the largest amount of gelatin possible and thereby reduce the amount of water which would evaporate during drying to reach a stable equilibrium throughout. However, with the use of high viscosity vehicles, very high bloom gelatin may be used, for example 280 bloom gelatin.
The same molecular weight criteria may apply to any of the other natural and synthetic macromolecules hereinbefore enumerated.
The type of products which can be adapted to our invention are extremely varied, including chemicals, foods and pharmaceutical compounds. Typical chemicals which can be incorporated in the matrix as the active ingredient include synthetic detergents as used in bubble baths and aromatic compounds as employed in room fresheners. Typical food type chemicals which may be employed are gravy mixes, food flavors and bouillon extract. Pharmaceuticals _ 9_ ~O-~.L~O~.
may include water-soluble or water-insoluble drugs, multivitamins and multi-vitamin-mineral mi~ctures, antihistanlines, decongestants, sleeping prepara-tions, tranquili~ers, laxatives, cough preparations, antacid preparations, smoking deterrents, antidiabetic agents, sedatives, suppositories, stimulants, and water-stable antibiotics.
The above principles of our inventioll are set forth in more detail by reference to the following specific examples, which are meant to be illustrative of these principles rather than limitations of the invention. Matrix components are given in grams per unit dosage form and percent by weight. The homo-genous solid dosage forms below were prepared by injection molding on a Model 1116 AC "Air Cylinder Honajector" described above, having an 11/16"
ram diameter and maximum shot capacity of 18 grams to form a dosage form of substantially spherical or oval shape.

ILLUSTRATIVE EXAMPLES OF THE INVENTION(1) Diphenhydramine - Antihistamine-Somnifacient (a) Components:
%
Diphenhydramine Hydrochloride0. 050 Gm. 2. 2 Gelatin MB (bloom 194) 1. 419 Gm. 62. 6 Glycerin 0. 653 Gm. 28. 8 Water 0. 145 Gm. 6. 4 - (b) Preparation Blend glycerin and gelatin. Stir in diphenhydramine hydro-chloride, dissolved in water, and mix until uniformly granu-lar. Inject ~ 180-200F with line pressure @ 80 PSI.
Injection pressure = 2710 PSI.

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(2) Phenolphthalcin - Laxative (a) Components:
Phenolphthalein 0.097 Gm. 4.3 - Gelatin MB (bloom 194) 1.387 Gm. 61.2 C Glycerin 0. 638 Gm. 28.1 Water 0.145 Gm. 6.4 (b) Preparation:
Dry blend phenolphthalein and gelatin. Blend in glycerin and add water. Mix until uni~ormly granular. Inject C 180-200~F with line.
10 pressure ~ 80 PSI. Injection pressure = 2710 PSI.

(3) Breath Freshener (a) Components:
Peppermint-Spearmint Flavor 0. 0100 Gm. 0,44 Gelatin MB (bloom 194) 1.1670 Gm. 51.50 Glycerin 0.7690 Gm. 33.90 Water 0.2920 Gm. 12.90 FD&C Red #2 0. 0014 Gm. 0. 06 Sodium Saccharin 0. 0272 Gm. 1.20 (b) Preparation:
Blend glycerin and gelatin. Combine flavor + dye + saccharin +
water and mix in until uniformly granular. Inject ~ 180-200F with line pressure ~ 80 PSI.
Injection pressure = 2710 PSI.

(4) Diphenhydramine - Antihistamine-Somnifacient (a) Components:
%
Diphenhydramine Hydrochloride0. 0500 Gm. 2.6 Polyvinyl Pyrrolidone (GAF Plasdone 1. 4865 Gm. 76. 6 K-29-32)~
Glycerin 0.1940 Gm. 10.0 Water 0.1940 Gm. 10.0 Ammonium Persulfate 0.0155 Gm. 0.8 ~arK
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, ~ - - '; -10~05 (b) Preparation:
Dry blend polyvinyl py~rolidone, ammonium persulfate, and drug and while mixing spray on glycerin + water. Inject 13 200-225F
with line pressure @ 80 PSI.
Injection pressure = 2710 PSI.
15) Ephedrine Sulfate - Decongestant (a) Components Ephedrine Sulfate 0. 0250 Gm.1. 27 Polyvinyl Alcohol Medium (duPont Elvanol~;rade 52-22, 21-25 cp, 4% sol'n ~3 20C, determined by - Hoeppler falling-ball method) 0. 5648 Gm. 28. 67 Glycerin 1. 0835 Gm.55. 00 Water 0. 295518 Gm. 15. 00 FD&C Blue #1 0. 001182 Gm. 0. 06 (b) Preparation:
Combine drug + dye ~ glycerin + water and add quickly to polyvinyl alcohol. Mix until uniformly granular. Inject G 2Z5F with line pressure ~S 80 PSI.
Injection pressure = Z710 PSI.
(6) Chloral Hydrate - Sedative and Soporific ~a) Components:
% . _ Chloral Hydrate 0. 6950 Gm.55. 600 Polyvinyl Alcohol Medium (duPont Elvanol~;rade 52-22, 21-25cp, 4% sol'n ~ 20G, determined by Hoeppler falling-ball method) 0. 3470 Gm. 27. 760 Glycerin 0. 0330 Gm.2. 640 Water 0. 1747 Gm.13. 976 FD&G Yellow #5 0. 0003 GmØ 024 (b) Preparation:
Dry blend polyvinyl alcohol ~ chloral hydrate, and mix in quickly water ~ glycerin ~ dye. Blend until uniformly granular, Inject Gl 150F with line pressure ~ 80-90 PSI. Injection pressure =
2710-3049 PSI.
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(7) Chloral Hydrate - Sedative and Soporific (a) Components:
f %
Chloral Hydrate 0. 6840 Gm. 55. 6 Polyvinyl Alcohol Low (duPont ; - Elvanol Grade 57-05~ 3. 5-5. 0 cp, 4% sol'n /3 20C determined by Hoe p pl e r falling - ball m ethod )0. 4476 Gm. 36. 4 Water 0. 0984 Gm. 8. 0 (b) Preparation Dry blend polyvinyl alcohol + chloral hydrate, and while mixing spray on water. Mix until uniformly granular. Inject @
125- 150 F with line pressure ~S 80 PSI.
Injection pressure = 2710 PSI.
(8) d-Methorphan Hydrobromide - Cough Preparation (a ) C omponents:
d-Methorphan HBr (10% adsorbate) 0. 1500 Gm. 13.44 Corn Starch (American Maize Products Co. Amylomaize V~
Pearl Starch) 0. 3860 Gm. 34. 62 - 20 Water 0. 2776 Gm. 24. 90 Polyacrylic Aci~ (Rohm & Haas Co., Acrysol A-5, 20 cp, 5% sol'n Brookfield viscosity) 0. 2230 Gm. 20. 00 Carboxyvinyl Polymer (B. F.
Goodrich Che~m. Co. .
Carbopol 934) 0. 0780 Gm. 7. 00 - FD&C Yellow #5 0. 0004 Gm. 0. 04 (b) Preparation Powder blend starch + carboxyvinyl polymer + d-Methorphan HBr.
Dissolve polyacrylic acid and dye in water and quickly add to powders. Mix until uniformly granular or doughy. Inject 150F with line pressure @ 80 PSI.
Injector pressure - 2710 PSI.

l~rc~e inorK5 (9) Isoprot~r~nol ~iydrochloride - Bronchodilator (a) Cornponents:
%
Isoproterenol Hydrochloride 0. 0100 Gm. 1. 01 Hydroxypropyl Cellulose (Hercules P-vd. Cc-., Klucel*GF, Visc. =
140-400 cp. ~ 25C in 2% sol'n Brookfield Visc. ) 0. 9400 Gm. 94. 95 Water 0. 0399 Gm. 4. 03 FD&C Red #3 0. 0001 Gm. 0. Ol (b) Preparation:
Blend hydroxypropyl cellulose + isoproterenol hydrochloride and while mixing spray on water + dye. Inject ~3 350~F with line pressure ~ 80 PSI.
Injection pressure - 2710 PSI.
(10) Dimenhydrinate - Antinauseant (a) Components %

Dimenhydrinate 0. 0500 Gm. 5.05 Hydroxypropyl Methylcellulose (Dow Chem. Co., Methocel*HG-60, Visc.
50 cp in 2% sol'n) 0. 5700 Gm. 57. 60 Propylene Glycol 0. 3300 Gm. 33. 30 - Water 0. 0399 Gm. 4. 03 FD8~C Violet ~1 0. 0001 Gm. 0. 01 (b) Preparation Blend Methocel*~ dimenhydrinate and mix in propylene glycol + water + dye. Mix until uniformly granular. Inject ~ 325F
with line pressure C~ 85 PSI.
Injection pressure = 2880 PSI.
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(11) Chlorphellira~ c .~ leate - Antihist2mille (a) Comp~ncnts:
%

Chlorpheniramine ~,Ialeate 0. 0040 Gm. 0. 40 Pectin (Sunkis t,*Citrus i~TF, Pure Grade, ~IW = 150,000 - 300,000) 0.4615 Gm. 46.00 Glycerin . 0. 3846 Gm. 38.30 Water 0. 1538 Gm. 15. 30 FD&C Red ~2 0. 0001 Gnt. 0. 01 (b) Preparation Blend pectin + chlorpheniramine maleate, mix in glycerin +
dye + water. ~Iix until uniformly granular. Inject @ 300F
with line pressure @ 85 PSI.
Injection pressure = 2880 PSI.
(12) Phenolphthalein- Laxative (a) Components ~o Phenolphthalein 0. 097 Gm. 9. 7 Polyethylene Oxide (Union Carbide, - Polyox*WSR-N-750, I~IW = 300, 000 visc. cps, C Z5C = 550-900 in 5%
sol'n) 0. 863 Gm. 86. 3 Water 0. 040 Gm. 4.0 (b) Preparation Blend Phenolphthalein + polyethylene oxide, spray on water, and mix until uniforrnly granular. Injcct ~ 200F ~vith line pressure ~ 85 PSI.
Injection pressure = 2880 PSI.
(13) Dimenhydrinate - Antinauseant (a) Components:
%
Dimenhydrinate 0. 0500 Gm. 5. 00 Promine~R (Central Soya, isoelectric isolated soy protein pH 4.6) 0. 5300 Gm. 53. 00 Glycerin 0. 3700 Gm. 37. 00 Water 0. 0496 Gm. 4.96 FD&C Blue #1 0. 0004 Gm. 0. 04 * a trade mark ~ ~Ai -15_ ` ;.

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Blelld din~cnhyclrin~te I Promille 1~ ld mix in solution of dye ~vater ~ lycerin until uniforn~ly ,,ranular. Inj~ct ~ 400F ~Vit]l line pressure ~ 85 PSi.
Injection pressure = 2880 PSI.
(14) Chlorpheniramille Malcate - ~ntihistamine (a) Compon~nts:
%

Chlorph~miramine Maleate 0. 0040 G~n. 0.32 Gum Arabic Po~vder, USP (Sargent-~Velch, MW = 240,000) 0.9375 Gm. 75.00 Glycerin 0. 2500 Gm. 20.00 Water 0.0580 Gm. 4. 64 FD&C Blue #1 0. 0005 Gm. 0. 04 (b) Preparation Blend gum arabic 1 chlorpheniramine maleate, mix in glycerin +
dye + ~vater. Mix until uniformly granular. Inject @~ 250F with line pressure ~ 85 PSI.
Injection pressure = ~880 PSI.
(15) Chlorpheniramine Maleate - Antihistamine (a) Components:
~o Chlorpheniramine Maleate 0. 0040 Gm. 0.32 Chondrus,*N. F. (S. B. Penick &
Co., Irish Moss) 0. 7142 Gm. 56.68 Glycerin 0. 4788 Gm. 38. 00 Water 0. 0630 Gm. 5. 00 (b) Preparation:
Dry blend Chondrus + chlorpheniramine maleate on Hobart mixer and mix in glycerin + water. Mix until uniformly granular or doughy. Inject C 275-300F ~vith line pressure ~5 85 PSI.
Injection pressure = 2880 PSI.

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Although the mechanism is not entirely understood, and we do not wish to be bound by theory, it appears that the macromolecular gel-lattice matrix reaches a moisture equilibrium throughout itself, Quite unexpectedly, with the system according to this invention, we have found that the dosage forms do not get tacky or dry out and become brittle when stored under ordinary conditions after substantial periods of time on the order of 6 - 7 months. From their con-dition at that time, the units have a projected life of 3 - 4 years, based on our experience. Since the finished dosage forms are uniform, homogenous and rigid, they are not susceptible to leaking, cracking, puncture, fracture, and distortion as are oil-vehicle soft gelatin capsules. The extended stability of our units is quit e unexpected in view of the extremely high affinity of gelatin for water, and water-containing compositions heretofore used. In addition, the dosage forms of the present invention provide for rapid action of the active in-gredient by virtue of their relatively high water content and absence of an inhi-bitory oil vehicle, even those which are old, by virtue of the fact that the water content is in equilibrium and is a relatively high value of from 5-20%.
It should be evident from the foregoing description and specific examples that many variations can be made within the scope of our invention without de-parting from the spirit thereof, and the scope of our invention is to be limited 20solely by the following claims.
We claim:

: -

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A unit dosage form comprising only a unitary solid molded body structure without a surrounding shell, said body structure consisting of a set rigid gel system of gelatin, casein, collagen, albumin, soya protein, or soya peptone in the form of a water-soluble macromolecular gel lattice matric which contains from at least 4% to as much as 20% by weight of water, and an active medicinal ingredient in aqueous solution, suspension or dispersion, the ratio of said active ingredient to said matrix being from 1:1 to 7:1 by weight, the water in said system being distributed homogeneously throughout and in moisture equilibrium throughout.

2. A unit dosage form as in claim 1, wherein an active ingredient is present as an emulsion in said aqueous system.

3. A unit dosage form as in claim 1, wherein an active ingredient is present as a suspension in said aqueous system.

4. A unit dosage form of claim 1 wherein said gel lattice matrix is gelatin.

5. A unit dosage form of claim 1 wherein said gel lattice matrix is low bloom gelatin.

6. A unit dosage form of claim 5 wherein said low bloom gelatin has a bloom value of 0 - 40.

7. A method for preparing an integral solid unit dosage form of high moisture content without a surrounding shell, said method comprises the steps of:
(1) mixing a medicinal compound as the active ingredient in aqueous solution, suspension, dispersion or mixture thereof having a 4-50% by weight of water and a water-soluble macromolecular compound selected from gelatin, casein, collagen, albumin, soya protein, and soya peptone to form a fluid melt of low air content, (2) Mechanically shaping individual integral unit dosage forms directly from said melt, and (3) reducing the moisture level of said dosage forms to about 4-20% by weight for defining a stable system of a rigid, water soluble macromolecular gel lattice matrix vehicle carrying said aqueous ingredient, said dosage form being in moisture equilibrium throughout, thereby retarding the tendency of said dosage forms to stick together, become brittle, soften and wrinkle as said dosage forms age.

8. A method as in claim 7, wherein said melt has a viscosity of from 6,200 CPS to above about 254,000 CPS.

9. A method as in claim 7, wherein said mixing step includes: mixing said macromolecular compound in powdered, flake, or lump form with water under low shear agitation, adding said active ingredient to said macromolecular compound water mixture in the form of aqueous dispersions thereof, aqueous suspensions thereof, aqueous solutions thereof, and mixtures thereof, and removing any air in said mixture by vacuum degassing thereof.

10. A method as in claim 7, wherein said mechanical shaping step includes extrusion into dies which cut and form the final shape of said unit dosage form.

11. A method as in claim 7, wherein said mechanical shaping step includes injection molding to form the final shape of said unit dosage form.