US3927196A

US3927196A - Soluble capsules

Info

Publication number: US3927196A
Application number: US449142A
Authority: US
Inventors: Marvin Hersh
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1971-07-02
Filing date: 1974-03-07
Publication date: 1975-12-16
Anticipated expiration: 1992-12-16

Abstract

Soluble capsules containing a conventional solid hydrophobic encapsulating lubricant, the individual particles of said lubricant being enrobed in a hydrophilic friable sheath are disclosed. The utilization of the enrobed solid lubricant with conventional encapsulating equipment makes possible the preparation of soluble capsules with improved dissolution times.

Description

[ Dec. 16, 1975 1 SOLUBLE CAPSULES {75] Inventor: Marvin Hersh, Strafford, Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

22 Filed: Mar. 7, 1974 21 Appl. No.: 449,142

Related US. Application Data [63] Continuation-in-part of Ser. No. 159,568, July 2.

1971, abandoned.

[52] US. Cl. 424/37 [51] Int. Cl. A6lJ 3/07; A61K 9/48 [58] Field of Search 424/37 [56] References Cited UNITED STATES PATENTS 3,210,208 10/1965 Grass et al. 106/148 3,382,150 5/1968 Grass et al. 424/32 3,518,343 6/1970 Welsh et a1. 424/44 3,518,344 6/1970 Welsh et a1. 424/44 3,518,345 6/1970 Dines et a1 424/44 OTHER PU BLlCATlONS Samyn et al. J. Pharm. Sci. 59(2): 169475 Feb. 1970 In Vitro Dissolution from Several Experimental C apsule Formulations.

Newton et al. J. Pharm. Pharmac. 23:452-453 (1971) The Effect of Additives on the Release of Drug from Hard Gelatin Capsules.

Dines et a1 264/300 Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-Robert Wiser [57] ABSTRACT Soluble capsules containing a conventional solid hydrophobic encapsulating lubricant, the individual particles of said lubricant being enrobed in a hydrophilic friable sheath are disclosed. The utilization of the enrobed solid lubricant with conventional encapsulating equipment makes possible the preparation of soluble capsules with improved dissolution times.

6 Claims, No Drawings SOLUBLE CAPSULES CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of US. patent application Ser. No. 159.568. filed July 2. 1971 now abandoned.

BACKGROUND OF THE INVENTION It is desirable in most pharmaceutical capsules. other than those specifically designed to release medication over a prolonged period of time, to obtain rapid and complete effect of the active constituents. The rate of dissolution or the rate at which the active constituents pass into solution is a critical property which indicates the rate of conversion of solid materials into the dissolved form necessary for absorption and activity. The inherent rate of dissolution of the active constituents should ideally be unaffected by the processing or additives required to convert the active constituents into a convenient, stable and easily ingestible oral dosage form. However, in practice it is usually necessary to include in the capsule composition, agents which impart physical characteristics essential for manufacture with existing encapsulation equipment, but which have adverse effects on dissolution rates.

The conventional method for making soluble capsules for pharmaceutical and other uses frequently requires the addition of a lubricant to the powder mix prior to the encapsulation procedure. Encapsulation is accomplished by mechanically separating the cap and body of a two-piece hard-walled capsule. then seating each open body in a counterbored hole in a circular metal ring. This metal ring is then rotated under a powder filled hopper, fitted with a rotary auger, whereupon the auger forces the powder mix into the open capsule body. Sealing is then accomplished by positioning the slightly larger diameter cap over the filled body and telescopically joining these two cylindrical, coaxial capsule elements by mechanical or pneumatic pressure.

During this entire encapsulation procedure, a lubricant is necessary to improve the flow characteristics of the dry powder mix when filling the capsule bodies, by helping to prevent binding of the rotary auger in the powder filled hopper [see, for example, H. Czetsch- Lindenwald and A. F. Asker, Pharm. Ind., 28, 614 (1965), who investigated the flow properties of pharmaceutical powders commonly filled into capsules and demonstrated how they can be improved by the addition of lubricants]. The presence of a lubricant component in the dry powder mix is essential in the operation, where the actual mechanical filling of the capsule bodies takes place [see, for example, G. Reier, R. Cohn, S. Rock, and F Wagenblast, Journal of Pharmaceutical Sciences, 57, 660 (1968)]. Here, high frictional and shearing forces are developed between the powder covered rotating metal ring containing already filled capsule bodies and the stationary hopper undersurface. Excess powder, which has not been deposited into the capsule bodies. accumulates to form a layer between these two metal surfaces. These frictional forces are a direct consequence of the frictional nature of the powder or composition being filled, and frequently, poorly lubricated formulations cause complete stoppage or binding of the mechanical filler when sufficient resistance is generated to cause stalling of the electric motor in the drive train. Also. variation in capsule fill 2 weight frequently results from inadequately lubricated powder mixes.

The lubricants generally used to decrease or eliminate these undesirable processing properties, are fine solid particles. typified by such hydrophobic materials as metallic stearates. fatty acids. talc, natural and synthetic waxes or liquids such as mineral oil.

The current technique for the addition of lubricant to a powder mix intended for encapsulation requires the homogeneous distribution of hydrophobic, non-adherent lubricant particles throughout the entire mix. Although the presence of a lubricant is necessary to help prevent binding and'stoppage of the rotary auger in the powder filled hopper. and is essential in the space between the ring and hopper, hydrophobic lubricant particles must be uniformly dispersed throughout the entire capsule contents. In subsequent use, the presence of the solid hydrophobic lubricant particles impedes the entrance of water or other fluids. with a consequent adverse effect on the disintegration, powder mix deaggregation and dissolution of the capsule contents.

The presence of solid hydrophobic lubricant particles in an excipient system surrounding active material which is intended for rapid dissolution is a negative design. The dispersal of fluid through intra-particular passages is desired to initiate dissolution of the active components: however, the presence of solid hydrophobic lubricant particles impedes this distribution of solvent in the filled capsule.

The value of reducing the hydrophobic characteristics of the capsule contents. thereby improving the dissolution rate of the capsule contents is apparent.

SUMMARY OF THE INVENTION The invention sought to be patented in a principal composition aspect resides in the concept of a unit-dosage form comprising a two-piece. hard-walled. telescopically joined, soluble gelatin capsule containing a powdered solid which comprises a conventional solid encapsulating lubricant, a substantial proportion of the particles of said lubricant being enrobed in a hydrophilic friable sheath.

The tangible embodiments of the principal composition aspect of the invention possess the applied use characteristic of being soluble gelatin capsules possessing improved disintegration and powder mix deaggregation characteristics as well as providing more rapid dissolution of the capsule contents, which are capable of preparation by standard encapsulating procedures.

The invention sought to be patented in a second composition aspect resides in the concept of a unit-dosage form comprising a two-piece hard-walled, telescopically joined, soluble gelatin capsule containing a powdered solid which comprises a medicament and a conventional solid encapsulating lubricant. a substantial proportion of the particles of said lubricant being enrobed in a hydrophilic friable sheath.

The tangible embodiments of the second composition'aspect of the invention possess the applied use characteristic of being soluble unit dosage forms possessing improved disintegration and powder mix deaggregation characteristics as well as providing more rapid dissolution of the capsule contents, thus being capable of supplying the contained medicament to the capsule recipient at an improved rate as compared to encapsulated dosage forms in use prior to this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In accordance with the present invention a method is now provided whereby conventional encapsulating equipment and standard encapsulating procedures are utilized to prepare two-piece. hard-walled. telescopically joined soluble gelatin capsules having improved disintegration characteristics.

The conventional encapsulating excipients such as fillers. glidants. disintegrants. and buffering agents. may be mixed with a specially prepared enrobed hydro phobic solid lubricant before encapsulation. The powdered conventional solid encapsulating lubricant has previously been treated to enclose a substantial proportion of the particles of said lubricant within a non hydrophobic. friable sheath or envelope. This relatively inelastic envelope is designed to selectively rupture only at areas of high friction or high shear during en capsulation. such as the contact surfaces of the ring and hopper. and remain intact in all other portions of the powder mix not subject to high shear or frictional forces. Shear. in this context. is considered as stress resulting from applied forces that cause two contiguous surfaces to slide relatively to each other in a direction parallel to their plane of contact. Thus. the entrapped solid hydrophobic lubricant released from the ruptured enrobed solid lubricant particles functions only where actually required. The solid enrobed lubricant particles which have not been subjected to frictional or shearing forces remain intact and present none of the antiadherent. hydrophobic properties of conventional. unprocesses lubricants. Thus. the subsequent desirable dispersal of fluids within the capsule (for example when it is administered to a host) is facilitated and the availability of the contained active ingredient is improved.

The designed mechanical function of this method may be visually indicated by dye tracers incorporated in the enrobed lubricant. Dye streaks appear only on the surface of the residual or excess powder layer on top of the ring containing the powder filled capsule bodies. thus indicating the desired rupture of the enrobed lubricant particle only in this area.

This invention accomplished a marked reduction in the total amount of unprocesses solid hydrophobic lubricant particles per capsule. with a consequent reduction of unwetable surface area. The conventional encapsulating lubricant is. in effect. continuously released or metered out on demand where needed. in direct proportion to the degree of shear involved.

The enrobed lubricants of the present invention can be prepared by a variety of processes. such as:

Dispersion of conventional encapsulating lubricant particles in molten mannitol. polyethylene glycol 4000. 6000 and 20.000. or other thermostable hydrophilic materials whereby milling or other methods of particle size reduction. after solidification. results in substantial entrapment of lubricant particles in a solid non-hydrophobic matrix:

Coating of the encapsulating lubricant particles with a hydrophilic material by a spray drying or spray cilling technique:

4 N. Tanaka. S. Takino. and l. Utsumi. J. Pharm. Sci.. 52. 664 I963 Any of the various conventional solid hydrophobic encapsulating lubricants may be used in this invention. Among these are magnesium stearate. calcium stearate. talcum. fatty acids. stearic acid. and powdered vegetable stearine. Other suitable encapsulating lubricants will readily suggest themselves and the utilization in the practice of the invention of any of a vast number of substances suitable as lubricants is well within the skill of the art.

Many hydrophilic substances may be utilized as the coating materials in the present invention. Among the hydrophilic enrobing materials contemplated by the present invention are such substances as gelatin. gum arabic. methyl cellulose. carboxymethylcellulose. polyvinyl alcohol. mannitol. polyethylene glycol 4000, 6000, and 20.000. and other hydrophilic materials which will be obvious to those skilled in the art. There is no criticality in the use of any particular lubricant or hydrophilic substance. The thickness of the enrobing material which surrounds the lubricant particles is also not critical. The frictional and shearing forces generated between the ring and hopper during encapsulation. for example. are extremely large and are more than sufficient to rupture the various sheath thicknesses which may be applied by the methods described in this invention and other methods known in the art. The optimal thickness of the friable sheath will vary with the particular substances utilized. or the particular coating procedures used; however. the optimal thickness. or optimal range of thicknesses for a particular combination of lubricant and sheathing material may be readily determined by those skilled in the art.

It will be apparent to those skilled in the art that the two-piece hard walled telescopically joined soluble gelatin capsules prepared utilizing the present invention may have various different shapes and sizes. Further. they may be subject to a polishing procedure or any other routine processes which have been carried out on such soluble gelatin capsules prior to this invention.

While it is the main object of this invention to provide an improved method of preparation of soluble pharmaceutical gelatin capsules which possess an improved dissolution rate. it will be obvious to those skilled in the art that this improved method may be applied to soluble gelatin capsules other than those which contain a medicament. Thus. soluble capsules containing coloring and flavoring materials. spices. detergents. and even placebo capsules may be prepared utilizing the improved method of this invention.

The term soluble gelatin capsule when used in this specification and claims means those capsules which undergo ready dissolution when placed in the environment of their intended use such as those typically and widely used for supplying a prem easured amount of drug. detergent. dye. etc.

The following non-limiting examples illustrate the best mode contemplated by the inventor of carrying out the processes of the invention.

EXAMPLE I 10% Magnesium Stearate Enrobed in Polyethylene Glycol 4000. U.S.P.

Polyethylene glycol 4000 g.) is heated until molten (6065 C. and dry. finely powdered magnesium EXAMPLE II 33% Magnesium Stearate Enrobed in Gelatin To a suspension of gelatin (40 g.) in water 200 g.) is added finely powdered magnesium stearate USP. (20

'-continued lngredient mg. per capsule Total weight 120.0

The availability of 7-chloro-1.3-dihydro-3-hydroxy- 'phenyl-2I-ll.4-benzodiazepin-2-one is indicated by continuously recorded spectrophotometric assay. T and T is time in minutes necessary for dissolution of 50 and 80%, respectively, of the total 7-chloro-l.3- dihydro-3-hydroxy-5-phenyl-2I-I l ,4-benzodiazepin- 2-one per capsule.

'7: in sol'n in soln T,-,., T,,,. in 30 mins. in 60 mins.

Control Capsule (con- 60+ 60+ 4 6 taining unprocessed lubricant) Capsule (made with 32 60+ 49 56 equivalent amount of enrobed lubricant) EXAMPLE III Calcium Stearate Enrobed in Gelatin by Spray Drying Dry powdered calcium stearate (10 g.) is suspended in a 1% gelatin solution (500 cc.) and the suspension is spray dried to remove the water. In this manner gelatin coated calcium stearate particles are obtained which are suitable for use as encapsulating lubricant in a conventional encapsulating procedure.

EXAMPLE IV Talc Enrobed in Polyethylene Glycol 6000 by Spray Chilling Dry powdered talc g.) is suspended in molten polyethylene glycol 6000 (250 g.) and stirred until homogeneous. This suspension is sprayed into a chilled chamber with cold air causing the polyethylene glycol 6000 to solidify about the tale particles In this manner talc particles coated with polyethylene glycol 6000 may be obtained which are suitable for use as an encapsulating lubricant in a conventional encapsulating procedure.

EXAMPLE V Tranquilizer capsules having the following composi tion and showing the superior dissolution characteris tics tabulated below are prepared in the following manner:

Ingredient mg. per capsule Gelatin Enrobed Lubricant (33"; Magnesium 19.8 stearatev LI. 5. P.) Lactose. L'. S. P. [85.2

The dissolution test method and equipment is described in .I. W. Poole, Drug Information Bull. 3, 8 1969).

The subject matter which the applicant regards as his invention is particularly pointed out and distinctly claimed as follows:

1. A unit dosage form comprising a two-piece. hardwalled, telescopically joined soluble gelatin capsule containing a powdered solid which comprises a conventional solid encapsulating lubricant composition consisting essentially of micropellets of finely divided particles of solid hydrophobic encapsulating lubricant selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, talcum. and powdered vegetable stearine, a substantial proportion of the particles of said lubricant being enrobed in a hydrophilic friable sheath, said sheathing material being selected from the group consisting of mannitol, polyethylene glycol 4000, 6000, and 20,000, gelatin, methyl cellulose, carboxymethylcellulose, gum arabic, and polyvinyl alcohol; said enrobed encapsulating lubricant imparting a reduction in dissolution time to said dosage form when incorporated in said dosage form, as compared to said lubricant when not enrobed.

2. The unit dosage form according to claim 1 wherein the lubricant is magnesium stearate and the hydrophilic friable sheath comprises gelatin.

3. The unit dosage form according to claim 1 wherein the lubricant is magnesium stearate and the hydrophilic friable sheath comprises polyethylene glycol 4000.

4. The unit dosage form according to claim 1 wherein the lubricant is calcium stearate and the hydrophilic friable sheath comprises gelatin.

5. The unit dosage form according to claim 1 wherein the lubricant is talc and the hydrophilic friable sheath comprises polyethylene glycol 6000.

6. A unit dosage form comprising a two-piece. hardwalled. telescopically joined soluble gelatin capsule containing a powdered solid which comprises a medicament and a conventional solid encapsulating lubri cant composition consisting essentially of micropellets of finely divided particles of solid hydrophobic encapsulating lubricant selected from the group consisting of magnesium stearate. calcium stearate, stearic acid. talcum, and powdered vegetable stearine. a substantial 8 arabic. and polyvinyl alcohol; said enrobed encapsulating lubricant imparting a reduction in dissolution time to said dosage form when incorporated in said dosage form. as compared to said lubricant when not enrobed. l=

Claims

1. A UNIT DOSAGE FORM COMPRISING A TWO-PIECE, HARD-WALLED TELESCOPICALLY JOINED SOLUBLE GELATIN CAPSULE CONTAINING A POWDERED SOLID WHICH COMPRISES A CONVENTIONAL SOLID ENCAPSULATING LUBRICANT COMPOSITION CONSISTING ESSENTIALLY OF MICROPELLETS OF FINELY DIVIDED PARTICLES OF SOLID HYDROPHOBIC ENCAPSULATING LUBRICANT SELECTED FROM THE GROUP CONSISTING OF MAGNESIUM STEARTE, CALCIUM STEARATE, STEARIC ACID, TALCUM, AND POWDERED VEGETABLE STEARINE, A SUBSTANTIAL PROPORTION OF THE PARTICLES OF SAID LUBRICANT BEING ENROBED IN A HYDROPHILIC FRIABLE SHEATH, SAID SHEATHING MATERIAL BEING SELECTED FROM THE GROUP CONSISTING OF MANNITOL, POLYETHYLENE GLYCOL 400, 6000, AND 20,000, GELATIN, METHYL CELLULOSE, CARBOXYMETHYLCELLULOSE, GUM ARABIC, AND POLYVINYL ALCOHOL, SAID ENROBED ENCAPSULATING LUBRICANT IMPARTING A RECUCTION IN DISSOLUTION TIME TO SAID DOSAGE FORM WHEN INCORPORATED IN SAID DOSAGE FORM, AS COMPARED TO SAID LUBRICANT WHEN NOT ENROBED.

6. A unit dosage form comprising a two-piece, hard-walled, telescopically joined soluble gelatin capsule containing a powdered solid which comprises a medicament and a conventional solid encapsulating lubricant composition consisting essentially of micropellets of finely divided particles of solid hydrophobic encapsulating lubricant selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, talcum, and powdered vegetable stearine, a substantial proportion of the particles of said lubricant being enrobed in a hydrophilic friable sheath, said sheathing material being selected from the group consisting of mannitol, polyethylene glycol 4000, 6000, and 20,000, gelatin, methyl cellulose, carboxymethylcellulose, gum arabic, and polyvinyl alcohol; said enrobed encapsulating lubricant imparting a reduction in dissolution time to said dosage form when incorporated in said dosage form, as compared to said lubricant when not enrobed.