FR2554418A1 - DOSAGE FORMS FOR CAPSULES - Google Patents

Abstract

A DOSAGE FORM FOR CAPSULES CONSISTING OF TWO RIGID HALF-SHELLS, CONTAINING SOLID, CREAMY OR LIQUID SUBSTANCES, ESPECIALLY FOR PHARMACEUTICAL USE, CONSISTING OF TWO OR MORE CAPSULES WHICH CAN BE EASILY SEPARATED IN A SAME DOSAGE OR PERMITTED. DIFFERENT MEDICINES. THE BONDS BETWEEN THE CAPSULES MAY BE FORMED SIMULTANEOUSLY WITH THESE CAPSULES IN themselves BY PRESSURE MOLDING TECHNIQUES CONSTITUTED OF THE SAME MATERIAL AS THE CAPSULES. THESE CAN BE DIVIDED BY BREAKING THE BINDINGS WHEN THE CAPSULES ARE NOT USED SIMULTANEOUSLY. THE CAPSULES MAY BE FORMED BY TWO OR MORE COMPARTMENTS, NOT SEPARABLE WITHIN THE CAPSULES, FOR THE FILLING OF THESE COMPARTMENTS WITH DIFFERENT MEDICINES. THE CAPSULES MAY BE MANUFACTURED BY PRESSURE MOLDING TECHNIQUES, FROM GELATINS, STARCH OR OTHER POLYMERS AND ALSO FROM MIXTURES OR FOAMS OF THESE POLYMERS.

Description

255441 8

DOSAGE FORMS FOR CAPSULES

  The present invention relates to a dosage form for capsules consisting of a rigid shell and intended to contain solid substances, creamy or liquid, especially for pharmaceutical use. The dosage form according to the invention consists of two or more capsules which are connected to each other. The bonds between the capsules can be manufactured simultaneously with these capsules by pressure molding techniques and can be formed from the same material as the capsules themselves. The capsules can be

separated by breaking these bonds.

  The capsules may comprise two or more non-separable compartments within each capsule so as to contain in

these, different drugs.

  Capsules both compartmentalized and divisible can be manufactured simultaneously to form units with multiple dosages

or platelets.

  Hard shell capsules for pharmaceutical use according to the prior art consist of a unit which comprises only one

  filling compartment, formed by a lid and a cylindrical body

  drique fitting axially to each other. Due to manufacturing limitations by the dip-molding process according to the prior art, these known-type capsules can not be connected to each other

during their elaboration.

  It is known that tablets provide a solution for patients, allowing them to choose the desired dosage by breaking the

compressed into pieces.

  With the present invention, it is possible to realize a

  combination of two or more drugs that can not be mixed

  In a tablet or in a capsule according to the prior art, it is known that these drugs tend to react with each other to produce inappropriate products. In the present invention, dosage forms for capsules can be designed to be divided into smaller units, which can then be swallowed furthermore and in accordance with the present invention, it is possible to make capsules which can be filled with two or more

different drugs.

  Articles according to the present invention can be formed by pressure molding of starch, hydrophilic polymers such as gelatin or starch derivatives, all having a low water content. The present invention refers more specifically to certain

  structures and shapes for molded pressure capsules, in particular

  for injection molded capsules. The present invention refers to a dosage form for divisible rigid shell capsules having a plurality of interconnected units, comprising a

  cover and a body capable of being assembled together,

  in that the bodies comprise a mutual connection, this connection having come from molding with the bodies, this connection being furthermore capable of being broken so as to separate the capsule by

  units, especially for the dosing of pharmaceutical products.

  The present invention also relates to a dosage form for a capsule with a rigid and compartmentalized shell, comprising a lid and a body, characterized in that this body comprises one or more internal separations integrally molded with it so as to form two or more compartments, especially for drugs arranged inside this body and this lid when assembled for

  Dosage of pharmaceutical products.

  The present invention also relates to a rigid shell capsule dosage plate having a plurality of capsules connected to each other, each having a lid and a body

  assembled together, characterized in that these capsules have a connection

  mutual injection molded with these capsules and capable of being broken so as to separate each capsule into individual elements,

  especially for dosages of pharmaceutical products.

  In a die casting process, particularly injection molding, it is important that the molding material

3 2554418

  presents the qualities of a thermoplastic material during the operation and that this material hardens quickly in the mold so that it can be ejected quickly without changing dimensions. This latter feature is an important factor in that the accuracy of many die-cast articles must be

  in very precise dimensional limits.

  The present invention also relates to capsule dosage forms as described hereinafter, characterized in that the dosage form is made by injection molding: (i) from a composition of a hydrophilic polymer or from a mixture of such polymers having a water content of from 5 to 5% by weight (based on the composition of the hydrophilic polymer) and, when formed from a gelatin composition, this has a water content between 10

  and 20% by weight (calculated with respect to the gel composition

  tin); and / or (ii) from starch or a starch composition having a water content of 5 to 25% by weight (calculated with respect to the starch composition). Preferably, the capsules according to the invention are produced at

  from starch and by injection molding.

  Injection molding of hydrophilic materials such as gelatin containing water has been described in the application for

European Patent Publication No. 92 908.

  The hydrophilic polymers are polymers having molecular weights of approximately 103 to 107 Dalton, having in their structure and / or side chains molecular groups, and capable of forming and / or participating in the formation of hydrogen bridges. These hydrophilic polymers have a water content of 5 to 25% based on the weight of the composition of the hydrophilic polymer and the working temperature for the injection molding of these polymers.

  is between 50 C and 190 C, preferably between 80 C and 190 C.

  Gelatin, like a hydrophilic polymer, is made from different types of gelatin, such as ossein made in an acidic or basic medium, pig skin in an acid medium or leather

  of cattle in basic medium. These types of gelatin have a molecular weight

  preferably between 10.000 and 2.times.10.sup.7 Dalton or a molecular weight of between 10.000 and 2.times.10.sup.6 and 10.times.10.sup.-6

4 2 5 5 4 4 1 8

  x 106 Dalton. Their water content is preferably between 10 and 19% and more particularly between 12 and 18% by weight, calculated by

compared to gelatin.

  All hydrophilic polymers, including gelatins, may contain various additives such as plasticizers, lubricants, binding agents and dyes, as described in published European Patent Application No. 92,908, with concentrations also indicated in US Pat. this European patent application. The polymers may also contain other additives, up to 95% but preferably not more than 30% by weight, such as proteins of the sunflower, bean, cotton seed, peanut, blood protein type. , egg, rape seed and acetylated derivatives thereof,

  gelatin, cross-linked gelatine, vinyl acetate, poly-

  saccharides such as cellulose, methylcellulose, hydroxypropyl-

  cellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose,

  hydroxyethylcellulose, sodium carboxymethylcellulose, agar

  agar, gum arabic; guar, dextran, chitin, polymoral

  tose, polyfructose, pectin, alginates, alginic acids,

  monosaccharides, preferably glucose, fructose, saccharine

  oligosaccharides of: preferably lactose, polyvinyl

  pyrrolidone, silicates, bentonite, carbonates and bicarbonates

  nates. Such hydrophilic polymers are in particular constituted by

  from hydroxypropyl-methylcellulosephthalate (HPMCP), polyvinyl

  tate-phthalate (PVAP), cellulose acetate acetyl phthalate (CAP), acrylates and

  of methacrylates (Eudragit), phthalated gelatin, gelatin

  swimming, crotonic acid and shellac. These polymers are preferred when enteric properties are required. They preferably contain 5 to 25% water, more preferably 15 to 22% by weight calculated on the weight of the dehydrated polymer. The preferred ones are HPMCP, PVAP and CAP, especially PVAP and CAP; the best is PVAP, all of which can be used in the injection molding process having a water content of 5 to 25%, and preferably

at 22% by weight ..

  Some of these polymers are non-thermoplastic and it is quite surprising that they can be molded under pressure according to the invention.

2554418

  Molding temperatures are between 50 C and 190 C and pressures between 600 and 3,000 x 10 N / m2. Classic devices

can be used.

  Preferably, a starch composition made from wheat, flour, ground meal, rice and tapioca is used. The starch contains about 0 to 100% amylose and about 100 to 0% amylopectin; preferably 0 to 70% amylose and about 100 to 30% amylopectin and more preferably potato starch and

corn starch.

  When in the following description, the terms "gelatin" or

  "starch" are used, these also include foams, starch modifications or derivatives and combinations thereof with other polymer compositions whose properties are acceptable

  for the manufacture of molded pressure capsules.

  The starch has a water content of 5 to 25%, and preferably 15 to

  22%, and especially 17 to 20%.

  This starch may contain various additives such as plastics

  lubricants, binding agents and coloring agents.

  as well as dilution agents. All these products are the

  same as those mentioned above for hydrophilic materials.

  The molding temperatures of the starch are between 80 C and 240 C, with pressures in a range extending from 600 to

3.000 x 105 N / m2.

  The starch containing water and possibly other additives, is molded at these temperatures and pressures in a manner in which

  itself known, with molding apparatuses also known.

  Those skilled in the art are likely to make such fabrications with die casting but also with extrusion, compression, vacuum forming, thermal forming, extrusion molding, polymer casting processes in combination with vacuum forming. Preferably, however, a

  injection molding is used.

  The advantages of the present invention will become apparent to one

  specialist in the field, considering the detailed description that follows

  with reference to the accompanying drawings.

  In the present description, it has appeared useful to group the

  embodiments of the present invention in three categories.

6 25 5 4 4 1 8

  1. Divisible capsule The divisible capsule form may be swallowed whole or

  can be separated into elements that can be swallowed individually

  dually. Under these conditions, the initial capsule as well as the elementary capsules resulting from its separation are in a state which is easy to swallow and which can be adapted according to

the scope of application.

  The capsule comprising a divisible rigid shell used for the dosage has a plurality of interconnected elements having a lid and a body capable of being joined together and containing medicaments, is characterized in that the body has a connecting blade, this connection being molded with the body so that it can be broken in order to separate the capsule into unitary elements,

  especially for a pharmaceutical dosage.

  Also, the covers may have a slat of mutual connection. Similarly; either of the capsule parts may be in the form of a bulb wall while the other capsule is in the form of a lid wall secured by

  pressure and heat with the previous one.

  One embodiment of this type of capsule is shown in FIGS. 1, 2, 3 and 4. In FIG. 1, along the line 2-2, the two bodies 1 are connected by a small joining strip. lids 2 are not connected. In FIG. 3, which is an exploded view of FIG. 1, the dosage form is shown after filling but before the covers 2 are put in place on the bodies 1. FIG. 4 is a side view of FIG. 3 after the lids 2 have been placed on the bodies 1. The embodiment shown in Figures 1 to 4, can be swallowed as a whole capsule in its initial state and this dosage form can also be swallowed after it has been separated into two units according to connection lantern 5, so that each of the unit elements obtained can be swallowed individually. The two unitary elements of the divisible capsule shown in FIGS. 1 to 4 can be filled with different drugs or with the same drug. When the capsule is filled with the same medicine, the dosed amount can be

7 25 5 4 4 1 8

  divided by breaking the two-piece form, when the capsule is filled with two different drugs - one in each unit element - the desired drug can be obtained after rupture of the capsule at the level of the coverslip. In order to identify the content of each unit element, the colors of each element may be different or the unitary elements may be different.

differently printed.

  The capsule parts 1 and 2 and the connecting strip 5 may be manufactured simultaneously by pressure molding, preferably by injection molding. The lamella 5 is formed

  in the same material as the capsule parts 1 and 2.

  Figures 5 and 6 show another embodiment of the capsule having four unitary elements. Figure 5 is a

  plan view and FIG. 6 a side view of the

  FIG. 5, showing four covers 2 and four bodies 1 connected by a weak connecting strip 5 so as to present rupture possibilities. The capsule according to this embodiment, can be swallowed in whole or in three, or in two or only by a unitary element. Also, the different unit elements of the capsule can be filled with different drugs or

with the same medicine.

  Other embodiments are shown in Figures 7 to 12.

  The reference numerals used in FIGS. 7 to 12 are the same as those used in FIGS. 1 to 6. In these embodiments, the bodies 1 and the covers 2 are connected by joining elements 5 as shown in FIGS. 11 and 12. The

  covers 2 can cover the bodies 1; also cover

  keys 2 may have a recess 6 instead of the slat 5 of

  The connection is housed in such a way that it is difficult to

  after the capsule has been separated into its

unitary elements.

  Another embodiment is shown in FIGS. 13 and 14 where the capsule has three unitary elements having a central portion and two outer portions, each of which again consists of a body 1 and a lid 2. In FIGS. 14, the outer parts have the shape of triangles. Alternatively, the outer portions of the embodiment of Figures 15 and 16 are in the form of semicircles. In the embodiments of

8 25 5 4418

  FIGS. 13 to 16, the bodies 1 are only connected by the lamellars

  the 5 while the lids 2 are separate pieces.

2. Compartmented capsule

  A compartmented capsule has two or more compartments

  for housing drugs. It can not be broken into unit elements but it can be filled with two or more different drugs to be swallowed simultaneously. It is an advantage of the die casting technique that the number of compartments is absolutely not limited to two but can

  to be as high as required by the type of application desired.

  The embodiment of a dosing capsule comprising a compartmentalised rigid shell consists of a lid and a

  body, characterized in that the body has one or more

  internal moldings with it so that they form two or more compartments, especially for drugs disposed within this body and lid

  when assembled, for pharmaceutical use.

  Such a compartmentalized capsule may also be characterized in that the body is tubular with an internal separation perpendicular to its axis and parallel to its opposite open ends, each of its open ends being closed by a lid so as to form a compartment, particularly for

  contain drugs for pharmaceutical use.

  Such a compartmentalized capsule can also be characterized in that the body and the lid are constituted by walls

  bulbs sealed by heat and pressure.

  One embodiment of this group is shown in FIGS. 17 and 18. FIG. 17 is an exploded perspective view of a compartmentalized capsule having a lid 2 and a body i with two internal compartments delimited by a partition 5. Each of these compartments contain different drugs. FIG. 18 is a sectional view of the compartmentalized capsule of FIG. 17 along the line 18-18, once closed, and showing the complete separation of the different drugs in the compartments 11 and

12.

  FIG. 19 is a top plan view of another embodiment of

  embodiment of a compartmentalised capsule according to the present invention.

  showing two lids 2 coming into axial abutment one

9 2 5 5 4 4 1 8

  against each other at their open ends.

  FIG. 20 is a sectional view of FIG. 19 according to FIG.

  20-20, showing the two covers 2 abutted against each other at their open ends. Inside these lids 2, there is provided a cylindrical body 1, separated by an integral molded disc, disposed therein

  two compartments 11 and 12 intended to contain medicinal

  different elements. After filling the compartments 11 and 12 with these drugs, each of the two covers 2 is placed telescopically on the body 1 at each of its open ends so as to confine the various drugs inside. For different therapeutic requirements, one of the lids may be made of a material that is soluble in the acidic secretions of the stomach; the other lid 2 and the body 1 can be made of an enteric material. In this case, one of the drugs contained in one of the compartments may be disintegrated inside the patient's stomach, while the different drug in the other compartment may be disintegrated in the intestinal tract of the patient. By varying the materials and / or the thickness of the covers 2 and the bodies 1, it is thus possible to obtain control of the disintegration rates of each compartment 11

and 12.

  According to another embodiment of the invention, the covers 2 and the bodies 1 can be joined so as to produce a continuous surface in their junction zone J, as in FIGS.

19 and 20.

  3. Capsule Plate A capsule pad consists of two or more capsules that are connected in such a way that each elemental unit can be broken and separated for use. The capsules of capsules are not intended to be swallowed but more generally provide an adequate disposal for storage when each

  elementary units have to be taken periodically. As a result

  Consequently, the number of globally connected elementary units is not limited because of the requirement of an easy faculty to be swallowed. The platelets of capsules may also be used for the Group 1 capsule group and the Group 2 capsule assembly, seen previously. This arrangement of hard shell dosage cap platelets having a plurality of connected capsules consisting of mutually engageable lids and bodies is characterized in that the capsules have a mutual connection which

  came from molding with these capsules and that can be later

  broken to separate the blister into capsules

  in particular for pharmaceutical dosages.

  One embodiment of this group is shown in Figures 21 and 22. Figure 21 is a top plan view showing the capsules aligned along their axes. FIG. 22 is a cross-section of FIG. 21 along the line 22-22 showing the capsule bodies 1 connected by lamellae 5 which are formed of the same material

  that the bodies 1 and which are obtained simultaneously by a technique

  die casting. The caps 2 of the capsules of the dosage plate are not connected to each other. The bodies 1 and the covers 2 can be both provided with locking means so as to ensure a resistance-resistant disposition.

separation.

  Another embodiment of the capsule wafer is shown in Figures 23 and 24. Figure 23 is a top plan view showing unit capsules arranged along a circle. Fig. 24 is a sectional view of Fig. 23 taken along line 24-24 showing the capsule bodies 1 connected by links 5 which can be made of the same material as the capsule bodies 1. These connecting elements 5 are manufactured simultaneously with the bodies 1. The bodies 1 and the covers 2 may together also be provided with means of

blocking.

  Another embodiment of the capsule wafer is shown in FIGS. 25 and 26 for effecting the combination of two different drugs. FIG. 25 is a top plan view showing capsules joined by bonds 5. FIG. 26 is a section of FIG. 25 taken along line 26-26, showing capsule bodies 1 when simultaneously formed by die casting. The lids 2 are not interconnected. Capsules are shown in a layout

11 2 5 5 4 4 1 8

  it 2554418 in two rows, so that two drugs can be placed inside the capsule bodies arranged on each side.

  Blister packs are a form known to contain

  pharmaceutical dosages and other products requiring high safety. According to another provision of the present invention, rigid shell capsules may be formed from components having a bottom wall and a wall of

  cover that are sealed together by heat and pressure

  if we. Then these compartments are filled with medicines

  ments. In this form of the invention, the components of the

  ampoules are made from hydrophilic polymers

  soluble in water and susceptible to digestion.

  FIG. 27 is a plan view of an embodiment of a wafer comprising capsules in the form of bulbs, in which these bulbs are delimited by a wall delimiting

  separate internal compartments 11, 12, 13 and 14 ... The final

  FIG. 28 is a section of FIG. 27 along line 28-28, showing the wall delimiting the compartments 10 on which a cover wall 15 is sealed by pressure and heat so as to seal the compartments 11, 12, 13 , 14 ... containing the drugs. At the junction of the wall 10 delimiting the bulbs with the covering wall 15, can

  perforations 16 should be provided in order to weaken the separa-

  FIGS. 29, 30, 31 and 32 show other embodiments of blister-shaped capsule wafers, using the same numerals of the ampoules compartments 13, 14.

  reference only in Figures 27 and 28.

  In Figs. 29 and 30, the capsule wafer is shown having an elongate cross-section as in a conventional embodiment and in which the bottom wall and the cover wall define symmetrical compartments 13 and 14. In Figs. 32, the capsule plate is shown such that each compartment 11 or 12 is subdivided into elementary compartments 17, 18, 19, 20 respectively, for

  contain inside different drugs.

12,2554,418

  All embodiments of the present invention may

  be made by means of injection molding machines in the

  that the material of the capsule is first melted in a plastic setting unit, and then injected into the mold. When the mold is opened, the dosage portions of the capsules are ejected. The processes of film casting, injection molding, compression molding, blow molding, immersion printing and other molding techniques can also be used for

  manufacture of capsules according to the present invention.

  The present invention may also include the sealing or bonding of the capsules when the two parts thereof are assembled. The sealing or bonding of the capsule parts provides additional security which, moreover, avoids the separation and the alteration of the capsules and which also makes the capsule

  tight against moisture, steam and gases.

  The capsules produced in accordance with the description of the

  The present invention can be used for pharmaceutical applications.

  as well as for exact quan- titative dosages of

  dyes, chemicals, spices, fermented combinations

  plants, fertilizers with protective substances, seeds, cosmetics and agricultural products, etc.

  It must therefore be understood that the above description has not been

  only by way of illustration and that the invention also extends to all modifications and equivalents of these provisions.

1 3

13 2 5 5 4 41 8

Claims (14)

  1. A dosage form for a rigid and divisible shell capsule, comprising a plurality of interconnected elementary members consisting of a mutually engagable body and lid, characterized in that the body has a molded connection with the body and being further likely to be   broken so as to separate the capsule in its elementary parts.   2.- divisible rigid shell capsule according to claim 1,   characterized in that the covers carry the connections.   3.- divisible rigid shell capsule according to claim 1,   characterized in that the bodies carry connections and cover them other connections.   4.- divisible rigid shell capsule according to claim 1, characterized in that one part of the capsules is formed by a wall of ampoules and the other part by a cover wall, sealed together by heat and pressure.   5. Dosage form for hard shell capsules according to claim 1, arranged in a wafer having a plurality of conrnected capsules, each having a body and a lid capable of being assembled mutually, these capsules having a connection between them, this connection Moreover, it is likely to be broken   to separate the capsule into individual elementary capsules.   6.- Plate of hard shell capsules according to the claim   5, characterized in that one part of the capsule is a wall of ampoules-and the other part of the capsule a covering wall, sealed by heat and pressure.   7.- Dosage form for capsules A rigid shell and compartment   body and lid, characterized in that the body a. one or more internal separations molded with it so as to form two or more compartments, in particular for medicaments contained inside the body and the lid when   these are assembled for pharmaceutical use.   8.- Dosage form for compartmentalized hard shell capsules   according to claim 7, characterized in that the body and the cover   The keys are connected together by a thin slat of connection that can be broken. 14 52554418   9.- Dosage form for compartmentalized hard shell capsules   according to one of claims 7 or 8, comprising a body and a cover   key, characterized in that the body has one or more parti-   internal moldings with it, so as to delimit two or more compartments for drugs inside the body   and the lid when they are assembled.   10. Capsule with rigid shell compartmentalized according to the   cation 9, characterized in that the body is tubular with a portion   internally perpendicular to its axis and parallel to both ends   open, each of these open ends being closed by a neck.   flange to form an internal compartment.   11.- Capsule with rigid shell compartmentalized according to the   cation 9, characterized in that the body is formed by a wall of ampoules and the lid by another wall, sealed by heat and the pressure.   12.- hard shell capsule divisible according to any one of   Claims 1 to 10, characterized in that it is formed by molding   under pressure: (i) from a composition of a hydrophilic polymer or a mixture of such polymers, having a water content of 5 to 25% by weight   weight (calculated with respect to the composition of the hydro-   phile) and, when formed from a gelatin composition, it has a water content of 10 to 20% by weight (calculated with respect to the gelatin composition); and / or (ii) from starch or a starch composition having a water content of 5 to 25% by weight (calculated with respect to the starch composition). 13.- divisible rigid shell capsule according to claim 12,   made from a starch composition.   14.- Application of a divisible rigid shell capsule according to   any of claims 1 to 13 for pharmaceutical use.   as well as for the exact quantitative determination of color   chemicals, spices, fertilizer compositions for plants, fertilizers with protective substances, seeds,   cosmetics or agricultural products.   15.- Dosage forms for capsules according to any one of   Claims 1 to 13, incorporating pharmaceutical products,   dyestuffs, chemical materials, spices, fertilizers   seeds, cosmetics or agricultural products.