CA1314480C - Mouldings made from pellets - Google Patents
Mouldings made from pelletsInfo
- Publication number
- CA1314480C CA1314480C CA000533393A CA533393A CA1314480C CA 1314480 C CA1314480 C CA 1314480C CA 000533393 A CA000533393 A CA 000533393A CA 533393 A CA533393 A CA 533393A CA 1314480 C CA1314480 C CA 1314480C
- Authority
- CA
- Canada
- Prior art keywords
- pellets
- composition
- binder
- moulds
- moulding
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2200/00—General characteristics or adaptations
- A61J2200/20—Extrusion means, e.g. for producing pharmaceutical forms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Processing And Handling Of Plastics And Other Materials For Molding In General (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Encapsulation Of And Coatings For Semiconductor Or Solid State Devices (AREA)
- Perforating, Stamping-Out Or Severing By Means Other Than Cutting (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Compounds Of Unknown Constitution (AREA)
- Preparation Of Clay, And Manufacture Of Mixtures Containing Clay Or Cement (AREA)
- Processing Of Solid Wastes (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to a delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a fusible matrix comprising a physiologically acceptable binder.
The invention relates to a delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a fusible matrix comprising a physiologically acceptable binder.
Description
~ 13~480 The present invention relates to pellet-containing pharmaceutical compositions.
Slow-release pellets containing an active substance are important in the area of orally administered medicaments. Usually, these pellets are introduced into gelatine push--fit capsules which the patient takes without opening. A major disadvantage of this way of administering an active substance is that the dosage of the slow-release drug can only be varied by an integral multiple Gf the dose contained in a single push-fit capsule. Thus, it is not possible for the patient to take a fraction of a dose unit of the drug under controlled conditions, i.e. to take a predeterminable and reproducible dose. There is also no guarantee that the remaining raction of the dose unit will be kept together saely.
Furthermore, it may be noted that for reasons of drug safety, many push-fit capsules are provided with a safety seal which results in the capsule being destroyed if it is opened.
Moreover, many patients find it distinctly unpleasant to swallow a drug in the form of a commercial gelatine capsule, since the capsule produces the sensation of a foreign body on being swallowed. ~his sensation can be so pronounced that it completely stops the swallowing mechanism. Clearly, in such a case it would be advantageous to he able to dissolve the capsule in a small amount of water and to swallow the pellets thus released as an "aqueous suspension".
:
1 3~4480 ~lowever, though this is hitherto not extensively known, commercial gelatine capsules will not dissolve in water at ambient temperature.
It is known to those skilled in the art that such pellets cannot be pressed to form tablets since the high pressure which has to be exerted in the press in order to achieve compaction leads to at least a partial destruction of the body of the ]0 pellets which may adversely affect active substance release behaviour of the pellet. The few attempts that have been made to develop a pellet which can withstand the high pressures required in tablet-pressing have entailed drastic limitations in the choice of the coating materials and the si~e of the pellets (see DE-A-23 36 21~).
It is therefore an aspect of the present invention to provide a pharmaceutical or veterinary composition made from pellets, which is manufactured by a process during which the high press pressures usually required for tablet-pressing do not have to be exerted.
Thus, according to one aspect of the present invention, we provide a delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a fusible matrix comprising a physiologically acceptable binder.
In the composition the pellets are embedded in a fusible (sinterable) matrix, and the composition optionally comprises means such as, for example, notches for easier subdivision.
The composition is preferably in the form of a moulding, more preferably in the form of a tablet or block of tablets, and preferably has a porous inner structure.
~ he t~rms fus:ible or sinterable matrix relate to a matrix which in the course of its manufacture is consolidated either by solidification of the melt or by sintering Ibrief heating) of a pulverulent material.
The term mou].ding, in the context of the present invention, encompasses not only tahlet-like or capsule-like shap~s but also all shapes which are suitable for oral administration or capable o~ division into forms suitable for oral administration.
For the composition of the lnvention pellets produced by conventional processes, such as dragee-making procasses or coating processes, are suitable. These include unretarded (that is to say directly soluble) pellets, pellets which have a coating resistant to gastric juices, for instance a la~quer coating, and slow-release pellets. The matrix comprises binders and, if appropriate, addi.tives such as are conventlonally used in galeni~al preparations. To allow ready disintegration of the composition to release the active substance containiny pellets from the matrix, the hinder should preferably be water-soluble or at least water-emulsi~iable, possibly depending on the pH, and should preferably have a melting point below 100C.
Preferred as binders are sugar alcohols Isuch as, for example, mannitol, xylitol and sorbitol~ as well as their esters, acids encountered in foodskuffs (such as, for example, tartaric acid, citric acid, malic acid, lactide and lact.ic acid), fatty ac~ds as well as their monoglycerides or diglycerides, :, ~
A
1 3 ~
~, sugar mixtures (such as, for e~ample, monosaccharides or disaccharides or glucose syrup), monoglycerides or diglycerides and their derivatives, and mixtures of the said substances.
For excipients having high melting points, it is preferable to use eutectic mixtures having a melting point below 100C.
One suitable binder for a fusible matrix is a mixture of sugar, lactose, sorbitol, starch syrup and water;
this mixture is referred to as "Basic Mix" in the literature. "Basic Mix" is a glassy mass having a softening point of 55 to 90C and a residual water content of about 0.5 to 2%.
Particularly preferred as binders are polyethylene glycols, such as, for example, Polywa~ 1500, Polywax * *
6000 and Polywax 20,000, which have a solidification point of between 25 and 60C.
Compositions according to the invention which readily disintegrate in an aqueous medium, releasing t'ne pellets, are especially preferred since these may be broken down before administration to produce a suspension of the pellets which may be swallowed more comfortably than a tablet. In this regard, mouldings which contain poLyethylene glycols as binders are preferred since the moulding rapidly disintegrates in an aqueous medium within a short time and the pellets can be swallowed comfortably as a kind of "aqueous suspension".
The invention thus also provides a pharmaceutical or veterinary form for pellets which form disintegrates in an aqueous medium within an acceptable period of time thereby releasing the pellets for easier ingestion.
*Trade Mark ~3~4~8~
Where the pellets are provided with a polymer shell to give delayed or controlled release of the active substance, the binder chosen should be one compatible with the polymer shell.
For use with certain active substances, the binder is preferably resistant to gastric juice.
According to another aspect of the present invention we provide a process for the preparation of a delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a matrix of a fusible, physiologically acceptable binder, comprising moulding or extruding a forming composition comprising said pellets and an at least partially fused physiologically acceptable binder.
In the case of extrusion the composition may be made by the extrusion of pellets in the binder, optionally with the extruded column being nipped at intervals to provide dividing lines defining individual tablets. The binder or mixture of binders should preferably have a broad softening point.
The mixing of the pellets with the binder and the subse~uent mechanical extrusion should not be so violent as to cause brealcing up of the extrusion or rupture of the slow-release coating.
According to a further aspect of the present invention we provide a process for the preparation of a moulding containing pellets which comprise an active substance and which are held in a matrix of a fusible, physiologically acceptable binder, said process comprising one of the following:
(a) introducing the pellets into moulds and subsequently ~31~80 f illing said moulds by pouring in a fused binder;
(b) coating the pellets with a binder, introducing the coated pellets into moulds and then heating briefly;
(c) mixing the pellets with a binder, introducing the mixture into moulds and then heating briefly; or (d) introducing the pellets together with a binder and a blowing agent into moulds and heating briefly.
In process (a) pellets which may, for example, have been manufactured by processes known from the literature and are provided with a slow-release coating are introduced into suitable moulds and an adequate amount Oe the molten binder is then poured into the mould. The amount of binder, which may contain galenical additives, that is to be used is conveniently between 5 and 50% by weight, preferably 10 - 25~ by weight, relative to the total weight of the pellets. When the material has cooled, the finished mouldings are taken from the mould and are packaged. Where appropriate, a release agent may be applied to the mould beEorehand to permit easier release. Mculds which permit simple removal of the moulding when it has cooled are particularly suitable for use in this process.
In process (b) the binder is applied as a coating~
in a suitable thickness, to pellets which may conveniently already have been retarded, e.g~ by the provision of a release delaying shell. Coating with the binder may be done, for example, by a dragee-coating process. The optimum thickness of the binder layer 1~14480 is essentially dependent on the size of the pellet and can be determined by simple experiments. The amount of binder used is conveniently between 5 and 50% by weight, preferably between 10 and 25%
by weight, based on the total weight of the pellets.
The pellets coated with the binder are introduced into moulds and are bonded together by brief heating, during which the binder briefly melts, at least at its surface. By brief heating it is meant that the heating should be sufficient for the binder on the surface of the coated pellets to melt sufficiently for adjacent pellets to be bound together on subsequent cooling. The heat re~uired for melting the binder may, in the case of suitably designed moulds, be applied via the mould, which, where appropriate, may additionally be provided with cooling devices.
If it is not possible to apply heat via the mould, the energy required for fusion may be applied from outside, for example by using microwave radiation or by using a heating device such as, for example, a simple oven. It is merely necessary to ensure that the retard layer of the pellets is not damaged by excessive heating.
In process (c) the pellets, conveniently already in retard form, are mixed with the binder and the - mixture is introduced into a mould. Further processing may be carried out as described for process (b) above.
In process (d) the pellets, conveniently already in retard form, are introduced, together with a binder, into a mould. Upon heating, the binder is uniformly distributed between the pellets by decomposition of the blowing agent, so that after cooling the desired moulding is obtained. Suitable 131~48~
as blowing agents are compounds which are pharmacologically safe and have a decomposition point in the range oE the melting point of the binder. Further, low-boiling solvents (such as, for example, hydrocarbons, halogenated hydrocarbons, perhalogenated hydrocarbons and alcohols) are suitable as blowing agents, provided they are compatible with the slow-release coating on the retarded pellets. If specially designed moulds are used, an inert gas, for example compressed air or nitrogen, may alternatively be used as the blowing agent.
On heating (sintering) the moulding, especially in the case of processes (b) and (c) as hereinbefore described, the softening of the loose mass of pellets causes a slight contraction in volume. To avoid crack formation and in order to achieve a uniform appearance it is advantageous to exert a slight pressure on the moulding while it is still warm, so as to assist the desired moulding action. However, it is, of course, obvious that the pressures exerted should be so slight that the pellets, and especially the slow-release coating of the pellets in retard formt are not damaged. Thus slight pressure is to be taken as meaning a pressure typically sufficient to cause smoothing down, polishing or densification. In a suitable embodiment it may suffice to vibrate the mould briefly in order to achieve densification.
In a particularly preferred embodiment of the process, blister foils (e.g. of thermally formed plastics film) with appropriate recesses for the mouldings (and, where appropriate, additional shapings to form division notches) are used.
The filling of these blister foils and the manufacture of the mouldings may be carried out in accordance with any one of processes (a~ to (d), the recesses in the foil simultaneously serving as the moulds.
~3~8Q
g When the mouldings have cooled, the blister foil is sealed with aluminium foil. When required for use, the mouldings are pressed out through the aluminium foil.
A moulding produced according to any one oE processes (b), (c) or (d) can, depending on the amount of binder used, have an uneven surface. However, this has no effect on the active substance release characteristics. If desired, an approximate]y uniform surface can be obtained on the moulding by a further application of binder or of a lacquer.
Mouldings produced by process (b) have a Porous inner structure. The bonding between the pellets occurs only at the points of contact of the binder coatings. Such mouldings therefore have particularly advantageous disintegration characteristics, since water or the relevant digestive fluids can more rapidly penetrate and dissolve the binder.
To delay disintegration of the mouldings, they may additionally be coated with a lacquer which is resistant to gastric juice or which has a retarding action. In this regard, it is also possible to manufacture the compositions of the invention using binders which are resistant to gastric juice, so that the pellet release only takes place on passage through the intestines.
The pharmaceutical composition is preferably divisible.
Such divisibility may be achieved, for example, by providing dividing notches by using moulds of appropriate shape, or subsequently by means of a heated tool, or by working the composition while it is still soft, i.e. not yet cooled, by means o~ a tool of appropriate design.
- 131~0 The present invent;on thus provides a pharmaceutical or veterinary form for pellets which can be subdivided one or more times and which permits such division with retention of the properties characteristic o~ the pellets, such as, for example, slow release.
An important advantage of the invention is that in the course of the manufacturing process according to the invention the pellets do not suffer any mechanical damage; accordingly, even after the composition has been subdivided, the pellets remain fully preserved~ Indeed, mouldings may be produced according to the invention from pellets which are not provided with a slow-release or gastric juice-resistant coating~
The invention will now be illustrated by means of the following non-li.miting Examples and with reference to the accompanying Drawings in which:
Figure 1 shows moulded tablets prepared according to Example l;
Figure 2 shows moulded tablets prepared according to Example 2;
Figure 3 shows a capsule-shaped tablet provided with a dividing notch;
Figure 4 shows moulded tablets prepared according to Example 4;
Figure 5 shows moulded tablets prepared according to Example 5;
Figure 6 shows moulded tablets prepared according to Example 6;
Figure 7 shows moulded strings of tablets;
Figure 8 shows moulded strings of tablets provided with an additional outer coating o~ polyethylene glycol powder;
Figure 9 shows moulded strings of tablets having undercuts, the right hand side showing spherical ~31~0 -- 11. --mouldings, the left hand side show;ng divisible mouldings; and Figure 10 shows further possible shapes for the compositions of the invention.
It should be noted that the compositions shown in the Figures are shown on an enlarged scale.
All percentages and ratios referred to herein are by weight unless otherwise stated.
131~80 Example 1 Pellets, manufactured by a conventional process by introducing an active substance into so-called "starter pellets" (which may be purchased) comprising sugar and/or corn starch, are introduced into the capsule receiving wells of a blister foil and Polywax 6000 is poured in. A typical tablet with a volume of about 0.68ml preferably contains 450-600mg of pellets. The pellets are pharmaceutical pellets containing an active substance such as theophylline and have a size o 0.8-2mm. lOO such pellets weigh 140mg and 100 such pellets with a retard coat weigh 160mg. Figure 1 shows the resultant tablets.
Example 2 Pellets from the same batch as for Example 1, mixed in the ratio of 1:1 with Polywax 6000 powder, are introduced into a capsule-like mould. The mould contents are fused at about 65C and pressed together.
The mould is removed ater cooling, releasing tablets as shown in F'igure 2.
Example 3 A dividing notch or notches may be introduced, producing tablets as shown in Figure 3.
Example 4 Pellets from the same batch as for Examples 1 and 2, together with 20% of Polywax 20,000, are warmed in a beaker and then stirred with a glass rod until solidification is complete~ The pellets thus coated with Polywax are introduced into a capsule-like mould having an upper and lower part and are slowly heated to about 65C, in the course of which the 4 8 ~
- l3 -mould is slowly pushed together. A~ter cooling, the mould is removed, releasing tablets as shown in Figure 4.
Example 5 15 - 20~ of Polywax 20,000 and a small amount of ammonium bicarbonate are introduced into the lower part of a two-part mould, and pe]lets, produced by a conventional process, are then introduced into the lower part of the mould. The quantity of ammonium bicarbonate used in strongly dependent on the viscosity of particular binder used. The quantity required can be determined by simple experiments.
In this particular case about 5m~ of ammonion bicarbonate per moulding is used. The upper part of the mould, which is provided with a plurality of aperatures, is then pushed on to the lower part and sintering is carried out at about 65C. The e~cess gas and Polywax is able to escape. Figure 5 shows Examples of tablets produced by this process.
_x~ e_ The mouldings are produced in the same manner as described in Example 4 except that the mixture of Polywax coated pellets introduced into the upper and lower parts of the mould contained 20 and 30%
respectively of Polywax 20,000. Figure 6 shows examples of such products.
Example 7 In addition to the Examples described above, rod shaped mouldings have been produced in order to emphasise the broad range of overall shapes possible for divisible compositions according to the invention.
.
Placebo pellets, having a weight of 25mg per 100 pellets, corresponding to a sieve fraction of 0~6 - 0.71 mm are provided, in a dragee-making kettle, with a coating of 20% by weight of polyethylene glycol 1500. These pellets have no active substance.
... . . . .
~314480 Moulds are produced by casting from silicone rubber, with the aid of precision-engineered rod patterns made from aluminium.
On directly sintering the above pellets in a microwave oven and lightly pressing the mould in by hand, the rods shown in Figure 7 are produced.
In order to seal the interstices between the pellets, the compositions of the invention may also be produced which consist of pellets provided with an additional "outer phase" or coating of polyethylene glycol powder. Such compositions are illustrated in Figure 8.
The use of plastically resilient moulds as described above also permits the manufacture of mouldings having under-cuts such as are shown in Figure 9.
The term "under-cut" refers to the situation when the mould opening is smaller than the greatest width of the moulding. Thus in order to remove the moulding the mould must either be broken or it must be elastic (e.g. made of silicone rubber).
Slow-release pellets containing an active substance are important in the area of orally administered medicaments. Usually, these pellets are introduced into gelatine push--fit capsules which the patient takes without opening. A major disadvantage of this way of administering an active substance is that the dosage of the slow-release drug can only be varied by an integral multiple Gf the dose contained in a single push-fit capsule. Thus, it is not possible for the patient to take a fraction of a dose unit of the drug under controlled conditions, i.e. to take a predeterminable and reproducible dose. There is also no guarantee that the remaining raction of the dose unit will be kept together saely.
Furthermore, it may be noted that for reasons of drug safety, many push-fit capsules are provided with a safety seal which results in the capsule being destroyed if it is opened.
Moreover, many patients find it distinctly unpleasant to swallow a drug in the form of a commercial gelatine capsule, since the capsule produces the sensation of a foreign body on being swallowed. ~his sensation can be so pronounced that it completely stops the swallowing mechanism. Clearly, in such a case it would be advantageous to he able to dissolve the capsule in a small amount of water and to swallow the pellets thus released as an "aqueous suspension".
:
1 3~4480 ~lowever, though this is hitherto not extensively known, commercial gelatine capsules will not dissolve in water at ambient temperature.
It is known to those skilled in the art that such pellets cannot be pressed to form tablets since the high pressure which has to be exerted in the press in order to achieve compaction leads to at least a partial destruction of the body of the ]0 pellets which may adversely affect active substance release behaviour of the pellet. The few attempts that have been made to develop a pellet which can withstand the high pressures required in tablet-pressing have entailed drastic limitations in the choice of the coating materials and the si~e of the pellets (see DE-A-23 36 21~).
It is therefore an aspect of the present invention to provide a pharmaceutical or veterinary composition made from pellets, which is manufactured by a process during which the high press pressures usually required for tablet-pressing do not have to be exerted.
Thus, according to one aspect of the present invention, we provide a delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a fusible matrix comprising a physiologically acceptable binder.
In the composition the pellets are embedded in a fusible (sinterable) matrix, and the composition optionally comprises means such as, for example, notches for easier subdivision.
The composition is preferably in the form of a moulding, more preferably in the form of a tablet or block of tablets, and preferably has a porous inner structure.
~ he t~rms fus:ible or sinterable matrix relate to a matrix which in the course of its manufacture is consolidated either by solidification of the melt or by sintering Ibrief heating) of a pulverulent material.
The term mou].ding, in the context of the present invention, encompasses not only tahlet-like or capsule-like shap~s but also all shapes which are suitable for oral administration or capable o~ division into forms suitable for oral administration.
For the composition of the lnvention pellets produced by conventional processes, such as dragee-making procasses or coating processes, are suitable. These include unretarded (that is to say directly soluble) pellets, pellets which have a coating resistant to gastric juices, for instance a la~quer coating, and slow-release pellets. The matrix comprises binders and, if appropriate, addi.tives such as are conventlonally used in galeni~al preparations. To allow ready disintegration of the composition to release the active substance containiny pellets from the matrix, the hinder should preferably be water-soluble or at least water-emulsi~iable, possibly depending on the pH, and should preferably have a melting point below 100C.
Preferred as binders are sugar alcohols Isuch as, for example, mannitol, xylitol and sorbitol~ as well as their esters, acids encountered in foodskuffs (such as, for example, tartaric acid, citric acid, malic acid, lactide and lact.ic acid), fatty ac~ds as well as their monoglycerides or diglycerides, :, ~
A
1 3 ~
~, sugar mixtures (such as, for e~ample, monosaccharides or disaccharides or glucose syrup), monoglycerides or diglycerides and their derivatives, and mixtures of the said substances.
For excipients having high melting points, it is preferable to use eutectic mixtures having a melting point below 100C.
One suitable binder for a fusible matrix is a mixture of sugar, lactose, sorbitol, starch syrup and water;
this mixture is referred to as "Basic Mix" in the literature. "Basic Mix" is a glassy mass having a softening point of 55 to 90C and a residual water content of about 0.5 to 2%.
Particularly preferred as binders are polyethylene glycols, such as, for example, Polywa~ 1500, Polywax * *
6000 and Polywax 20,000, which have a solidification point of between 25 and 60C.
Compositions according to the invention which readily disintegrate in an aqueous medium, releasing t'ne pellets, are especially preferred since these may be broken down before administration to produce a suspension of the pellets which may be swallowed more comfortably than a tablet. In this regard, mouldings which contain poLyethylene glycols as binders are preferred since the moulding rapidly disintegrates in an aqueous medium within a short time and the pellets can be swallowed comfortably as a kind of "aqueous suspension".
The invention thus also provides a pharmaceutical or veterinary form for pellets which form disintegrates in an aqueous medium within an acceptable period of time thereby releasing the pellets for easier ingestion.
*Trade Mark ~3~4~8~
Where the pellets are provided with a polymer shell to give delayed or controlled release of the active substance, the binder chosen should be one compatible with the polymer shell.
For use with certain active substances, the binder is preferably resistant to gastric juice.
According to another aspect of the present invention we provide a process for the preparation of a delayed release pharmaceutical or veterinary composition comprising pellets which comprise an active substance and which are held in a matrix of a fusible, physiologically acceptable binder, comprising moulding or extruding a forming composition comprising said pellets and an at least partially fused physiologically acceptable binder.
In the case of extrusion the composition may be made by the extrusion of pellets in the binder, optionally with the extruded column being nipped at intervals to provide dividing lines defining individual tablets. The binder or mixture of binders should preferably have a broad softening point.
The mixing of the pellets with the binder and the subse~uent mechanical extrusion should not be so violent as to cause brealcing up of the extrusion or rupture of the slow-release coating.
According to a further aspect of the present invention we provide a process for the preparation of a moulding containing pellets which comprise an active substance and which are held in a matrix of a fusible, physiologically acceptable binder, said process comprising one of the following:
(a) introducing the pellets into moulds and subsequently ~31~80 f illing said moulds by pouring in a fused binder;
(b) coating the pellets with a binder, introducing the coated pellets into moulds and then heating briefly;
(c) mixing the pellets with a binder, introducing the mixture into moulds and then heating briefly; or (d) introducing the pellets together with a binder and a blowing agent into moulds and heating briefly.
In process (a) pellets which may, for example, have been manufactured by processes known from the literature and are provided with a slow-release coating are introduced into suitable moulds and an adequate amount Oe the molten binder is then poured into the mould. The amount of binder, which may contain galenical additives, that is to be used is conveniently between 5 and 50% by weight, preferably 10 - 25~ by weight, relative to the total weight of the pellets. When the material has cooled, the finished mouldings are taken from the mould and are packaged. Where appropriate, a release agent may be applied to the mould beEorehand to permit easier release. Mculds which permit simple removal of the moulding when it has cooled are particularly suitable for use in this process.
In process (b) the binder is applied as a coating~
in a suitable thickness, to pellets which may conveniently already have been retarded, e.g~ by the provision of a release delaying shell. Coating with the binder may be done, for example, by a dragee-coating process. The optimum thickness of the binder layer 1~14480 is essentially dependent on the size of the pellet and can be determined by simple experiments. The amount of binder used is conveniently between 5 and 50% by weight, preferably between 10 and 25%
by weight, based on the total weight of the pellets.
The pellets coated with the binder are introduced into moulds and are bonded together by brief heating, during which the binder briefly melts, at least at its surface. By brief heating it is meant that the heating should be sufficient for the binder on the surface of the coated pellets to melt sufficiently for adjacent pellets to be bound together on subsequent cooling. The heat re~uired for melting the binder may, in the case of suitably designed moulds, be applied via the mould, which, where appropriate, may additionally be provided with cooling devices.
If it is not possible to apply heat via the mould, the energy required for fusion may be applied from outside, for example by using microwave radiation or by using a heating device such as, for example, a simple oven. It is merely necessary to ensure that the retard layer of the pellets is not damaged by excessive heating.
In process (c) the pellets, conveniently already in retard form, are mixed with the binder and the - mixture is introduced into a mould. Further processing may be carried out as described for process (b) above.
In process (d) the pellets, conveniently already in retard form, are introduced, together with a binder, into a mould. Upon heating, the binder is uniformly distributed between the pellets by decomposition of the blowing agent, so that after cooling the desired moulding is obtained. Suitable 131~48~
as blowing agents are compounds which are pharmacologically safe and have a decomposition point in the range oE the melting point of the binder. Further, low-boiling solvents (such as, for example, hydrocarbons, halogenated hydrocarbons, perhalogenated hydrocarbons and alcohols) are suitable as blowing agents, provided they are compatible with the slow-release coating on the retarded pellets. If specially designed moulds are used, an inert gas, for example compressed air or nitrogen, may alternatively be used as the blowing agent.
On heating (sintering) the moulding, especially in the case of processes (b) and (c) as hereinbefore described, the softening of the loose mass of pellets causes a slight contraction in volume. To avoid crack formation and in order to achieve a uniform appearance it is advantageous to exert a slight pressure on the moulding while it is still warm, so as to assist the desired moulding action. However, it is, of course, obvious that the pressures exerted should be so slight that the pellets, and especially the slow-release coating of the pellets in retard formt are not damaged. Thus slight pressure is to be taken as meaning a pressure typically sufficient to cause smoothing down, polishing or densification. In a suitable embodiment it may suffice to vibrate the mould briefly in order to achieve densification.
In a particularly preferred embodiment of the process, blister foils (e.g. of thermally formed plastics film) with appropriate recesses for the mouldings (and, where appropriate, additional shapings to form division notches) are used.
The filling of these blister foils and the manufacture of the mouldings may be carried out in accordance with any one of processes (a~ to (d), the recesses in the foil simultaneously serving as the moulds.
~3~8Q
g When the mouldings have cooled, the blister foil is sealed with aluminium foil. When required for use, the mouldings are pressed out through the aluminium foil.
A moulding produced according to any one oE processes (b), (c) or (d) can, depending on the amount of binder used, have an uneven surface. However, this has no effect on the active substance release characteristics. If desired, an approximate]y uniform surface can be obtained on the moulding by a further application of binder or of a lacquer.
Mouldings produced by process (b) have a Porous inner structure. The bonding between the pellets occurs only at the points of contact of the binder coatings. Such mouldings therefore have particularly advantageous disintegration characteristics, since water or the relevant digestive fluids can more rapidly penetrate and dissolve the binder.
To delay disintegration of the mouldings, they may additionally be coated with a lacquer which is resistant to gastric juice or which has a retarding action. In this regard, it is also possible to manufacture the compositions of the invention using binders which are resistant to gastric juice, so that the pellet release only takes place on passage through the intestines.
The pharmaceutical composition is preferably divisible.
Such divisibility may be achieved, for example, by providing dividing notches by using moulds of appropriate shape, or subsequently by means of a heated tool, or by working the composition while it is still soft, i.e. not yet cooled, by means o~ a tool of appropriate design.
- 131~0 The present invent;on thus provides a pharmaceutical or veterinary form for pellets which can be subdivided one or more times and which permits such division with retention of the properties characteristic o~ the pellets, such as, for example, slow release.
An important advantage of the invention is that in the course of the manufacturing process according to the invention the pellets do not suffer any mechanical damage; accordingly, even after the composition has been subdivided, the pellets remain fully preserved~ Indeed, mouldings may be produced according to the invention from pellets which are not provided with a slow-release or gastric juice-resistant coating~
The invention will now be illustrated by means of the following non-li.miting Examples and with reference to the accompanying Drawings in which:
Figure 1 shows moulded tablets prepared according to Example l;
Figure 2 shows moulded tablets prepared according to Example 2;
Figure 3 shows a capsule-shaped tablet provided with a dividing notch;
Figure 4 shows moulded tablets prepared according to Example 4;
Figure 5 shows moulded tablets prepared according to Example 5;
Figure 6 shows moulded tablets prepared according to Example 6;
Figure 7 shows moulded strings of tablets;
Figure 8 shows moulded strings of tablets provided with an additional outer coating o~ polyethylene glycol powder;
Figure 9 shows moulded strings of tablets having undercuts, the right hand side showing spherical ~31~0 -- 11. --mouldings, the left hand side show;ng divisible mouldings; and Figure 10 shows further possible shapes for the compositions of the invention.
It should be noted that the compositions shown in the Figures are shown on an enlarged scale.
All percentages and ratios referred to herein are by weight unless otherwise stated.
131~80 Example 1 Pellets, manufactured by a conventional process by introducing an active substance into so-called "starter pellets" (which may be purchased) comprising sugar and/or corn starch, are introduced into the capsule receiving wells of a blister foil and Polywax 6000 is poured in. A typical tablet with a volume of about 0.68ml preferably contains 450-600mg of pellets. The pellets are pharmaceutical pellets containing an active substance such as theophylline and have a size o 0.8-2mm. lOO such pellets weigh 140mg and 100 such pellets with a retard coat weigh 160mg. Figure 1 shows the resultant tablets.
Example 2 Pellets from the same batch as for Example 1, mixed in the ratio of 1:1 with Polywax 6000 powder, are introduced into a capsule-like mould. The mould contents are fused at about 65C and pressed together.
The mould is removed ater cooling, releasing tablets as shown in F'igure 2.
Example 3 A dividing notch or notches may be introduced, producing tablets as shown in Figure 3.
Example 4 Pellets from the same batch as for Examples 1 and 2, together with 20% of Polywax 20,000, are warmed in a beaker and then stirred with a glass rod until solidification is complete~ The pellets thus coated with Polywax are introduced into a capsule-like mould having an upper and lower part and are slowly heated to about 65C, in the course of which the 4 8 ~
- l3 -mould is slowly pushed together. A~ter cooling, the mould is removed, releasing tablets as shown in Figure 4.
Example 5 15 - 20~ of Polywax 20,000 and a small amount of ammonium bicarbonate are introduced into the lower part of a two-part mould, and pe]lets, produced by a conventional process, are then introduced into the lower part of the mould. The quantity of ammonium bicarbonate used in strongly dependent on the viscosity of particular binder used. The quantity required can be determined by simple experiments.
In this particular case about 5m~ of ammonion bicarbonate per moulding is used. The upper part of the mould, which is provided with a plurality of aperatures, is then pushed on to the lower part and sintering is carried out at about 65C. The e~cess gas and Polywax is able to escape. Figure 5 shows Examples of tablets produced by this process.
_x~ e_ The mouldings are produced in the same manner as described in Example 4 except that the mixture of Polywax coated pellets introduced into the upper and lower parts of the mould contained 20 and 30%
respectively of Polywax 20,000. Figure 6 shows examples of such products.
Example 7 In addition to the Examples described above, rod shaped mouldings have been produced in order to emphasise the broad range of overall shapes possible for divisible compositions according to the invention.
.
Placebo pellets, having a weight of 25mg per 100 pellets, corresponding to a sieve fraction of 0~6 - 0.71 mm are provided, in a dragee-making kettle, with a coating of 20% by weight of polyethylene glycol 1500. These pellets have no active substance.
... . . . .
~314480 Moulds are produced by casting from silicone rubber, with the aid of precision-engineered rod patterns made from aluminium.
On directly sintering the above pellets in a microwave oven and lightly pressing the mould in by hand, the rods shown in Figure 7 are produced.
In order to seal the interstices between the pellets, the compositions of the invention may also be produced which consist of pellets provided with an additional "outer phase" or coating of polyethylene glycol powder. Such compositions are illustrated in Figure 8.
The use of plastically resilient moulds as described above also permits the manufacture of mouldings having under-cuts such as are shown in Figure 9.
The term "under-cut" refers to the situation when the mould opening is smaller than the greatest width of the moulding. Thus in order to remove the moulding the mould must either be broken or it must be elastic (e.g. made of silicone rubber).
Claims (14)
1. A delayed release pharmaceutical or veterinary composition in dosage unit form, the units being porous, the composition including pressure-sensitive pellets that comprise a pharmaceutically or veterinarily active substance and are held in a fusible matrix of a physiologically acceptable binder.
2. A composition as claimed in claim 1 being in the form of a moulding.
3. A composition as claimed in claim 1 being in the form of a tablet.
4. A composition as claimed in claim 1 including means for subdivision.
5. A composition as claimed in claim 1 capable of readily disintegrating in an aqueous medium whereby to release said pellets.
6. A composition as claimed in claim 1 wherein said binder is water-soluble or water-emulsifiable.
7. A composition as claimed in claim 6 wherein said hinder is a polyethylene glycol
8. A composition as claimed in claim 1 wherein said binder is resistant to gastric juice.
15a
15a
9. A composition as claimed in claim 1 further provided with a gastric juice resistant lacquer coating.
10. A composition as claimed in claim 1 wherein said pellets are in retard form.
11. A process for the preparation of a composition as claimed in claim 1 comprising moulding or extruding a forming composition comprising said pellets and at least partially fused physiologically acceptable binder.
12. A process for the preparation of a moulding containing pellets which comprise an active substance and which are held in a matrix of a fusible, physiologically acceptable binder, said process comprising one of the following:
(a) introducing the pellets into moulds and subsequently filling said moulds by pouring in a fused binder;
(b) coating the pellets with a binder, introducing the coated pellets into moulds and then heating briefly;
(c) mixing the pellets with a binder, introducing the mixture into moulds and then heating briefly; or (d) introducing the pellets together with a binder and a blowing agent into moulds and heating briefly;
thereby to obtain a moulding having a porous structure that decomposes rapidly in aqueous media.
(a) introducing the pellets into moulds and subsequently filling said moulds by pouring in a fused binder;
(b) coating the pellets with a binder, introducing the coated pellets into moulds and then heating briefly;
(c) mixing the pellets with a binder, introducing the mixture into moulds and then heating briefly; or (d) introducing the pellets together with a binder and a blowing agent into moulds and heating briefly;
thereby to obtain a moulding having a porous structure that decomposes rapidly in aqueous media.
13. A process as claimed in claim 12 further comprising exerting a slight pressure on said moulding while it is still warm, whereby to assist the moulding action, to avoid cracks and to achieve a substantially uniform appearance.
14. A process as claimed in claim 12 or 13 wherein the walls of a blister foil axe used as said moulds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863610878 DE3610878A1 (en) | 1986-04-01 | 1986-04-01 | PELLET SHAPES |
| DEP3610878.2 | 1986-04-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1314480C true CA1314480C (en) | 1993-03-16 |
Family
ID=6297660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000533393A Expired - Fee Related CA1314480C (en) | 1986-04-01 | 1987-03-31 | Mouldings made from pellets |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0239983B1 (en) |
| JP (1) | JPS638327A (en) |
| KR (1) | KR950002881B1 (en) |
| AT (1) | ATE69547T1 (en) |
| AU (1) | AU600712B2 (en) |
| CA (1) | CA1314480C (en) |
| DE (2) | DE3610878A1 (en) |
| DK (1) | DK162887A (en) |
| ES (1) | ES2027246T3 (en) |
| FI (1) | FI94313C (en) |
| GR (1) | GR3003661T3 (en) |
| IL (1) | IL82065A0 (en) |
| MX (1) | MX5814A (en) |
| NO (1) | NO175513C (en) |
| NZ (1) | NZ219823A (en) |
| PT (1) | PT84604B (en) |
| ZA (1) | ZA872326B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2577080Y2 (en) * | 1991-09-10 | 1998-07-23 | 武田薬品工業株式会社 | Dividable solid |
| GB9422154D0 (en) | 1994-11-03 | 1994-12-21 | Euro Celtique Sa | Pharmaceutical compositions and method of producing the same |
| US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| AUPP279698A0 (en) * | 1998-04-03 | 1998-04-30 | Sunscape Developments Limited | Sustained release formulation |
| DE19918325A1 (en) | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives |
| US6982094B2 (en) | 2001-09-28 | 2006-01-03 | Mcneil-Ppc, Inc. | Systems, methods and apparatuses for manufacturing dosage forms |
| US6837696B2 (en) | 2001-09-28 | 2005-01-04 | Mcneil-Ppc, Inc. | Apparatus for manufacturing dosage forms |
| US7217381B2 (en) | 2001-09-28 | 2007-05-15 | Mcneil-Ppc, Inc. | Systems, methods and apparatuses for manufacturing dosage forms |
| US7838026B2 (en) | 2001-09-28 | 2010-11-23 | Mcneil-Ppc, Inc. | Burst-release polymer composition and dosage forms comprising the same |
| US7122143B2 (en) | 2001-09-28 | 2006-10-17 | Mcneil-Ppc, Inc. | Methods for manufacturing dosage forms |
| ATE376826T1 (en) | 2001-09-28 | 2007-11-15 | Mcneil Ppc Inc | MODIFIED RELEASE PHARMACEUTICAL FORMS |
| US7807197B2 (en) | 2002-09-28 | 2010-10-05 | Mcneil-Ppc, Inc. | Composite dosage forms having an inlaid portion |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2996431A (en) * | 1953-12-16 | 1961-08-15 | Barry Richard Henry | Friable tablet and process for manufacturing same |
| FR1540950A (en) * | 1967-04-27 | 1968-10-04 | Process for packaging oral absorbable medicinal substances | |
| DE1766546C3 (en) * | 1968-06-11 | 1974-11-28 | Karl Gunnar Lidingoe Eriksson | Process for the production of solid drug preparations in the form of tablets or tablets |
| NL6808619A (en) * | 1968-06-19 | 1969-12-23 | ||
| DK123806B (en) * | 1970-06-08 | 1972-08-07 | Pharmacia As | Process for the preparation of tablets or pills with slow release of an active substance. |
| GB1425550A (en) * | 1973-04-25 | 1976-02-18 | Alza Corp | Device for releasing active agent and process for producing the same |
| DE2336218C3 (en) * | 1973-07-17 | 1985-11-14 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Oral dosage form |
| SE414386B (en) * | 1976-03-10 | 1980-07-28 | Aco Laekemedel Ab | VIEW TO PREPARE AND AT THE SAME PACKAGE PHARMACEUTICAL DOSAGE UNITS |
| DE2620456A1 (en) * | 1976-05-08 | 1977-11-10 | Enterofagos Gmbh | Tablets contg. discrete granules esp. of pectin - are bonded together by fillers contg. vitamins and trace elements and give exact dosage |
| US4258027A (en) * | 1979-03-26 | 1981-03-24 | Mead Johnson & Company | Multi-fractionable tablet structure |
| DE3532692A1 (en) * | 1985-09-13 | 1987-03-19 | Boehringer Mannheim Gmbh | METHOD FOR PRODUCING TABLETS FROM PELLETS |
-
1986
- 1986-04-01 DE DE19863610878 patent/DE3610878A1/en not_active Ceased
-
1987
- 1987-03-30 FI FI871378A patent/FI94313C/en not_active IP Right Cessation
- 1987-03-30 KR KR1019870002929A patent/KR950002881B1/en not_active IP Right Cessation
- 1987-03-31 IL IL82065A patent/IL82065A0/en not_active IP Right Cessation
- 1987-03-31 DK DK162887A patent/DK162887A/en not_active IP Right Cessation
- 1987-03-31 NO NO871350A patent/NO175513C/en unknown
- 1987-03-31 NZ NZ219823A patent/NZ219823A/en unknown
- 1987-03-31 CA CA000533393A patent/CA1314480C/en not_active Expired - Fee Related
- 1987-03-31 ES ES198787104716T patent/ES2027246T3/en not_active Expired - Lifetime
- 1987-03-31 DE DE8787104716T patent/DE3774601D1/en not_active Expired - Lifetime
- 1987-03-31 EP EP87104716A patent/EP0239983B1/en not_active Expired - Lifetime
- 1987-03-31 AT AT87104716T patent/ATE69547T1/en not_active IP Right Cessation
- 1987-03-31 MX MX581487A patent/MX5814A/en unknown
- 1987-03-31 JP JP62079534A patent/JPS638327A/en active Pending
- 1987-03-31 ZA ZA872326A patent/ZA872326B/en unknown
- 1987-04-01 AU AU70956/87A patent/AU600712B2/en not_active Ceased
- 1987-04-01 PT PT84604A patent/PT84604B/en not_active IP Right Cessation
-
1992
- 1992-01-27 GR GR920400090T patent/GR3003661T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI94313B (en) | 1995-05-15 |
| JPS638327A (en) | 1988-01-14 |
| GR3003661T3 (en) | 1993-03-16 |
| FI871378A0 (en) | 1987-03-30 |
| KR870009719A (en) | 1987-11-30 |
| PT84604A (en) | 1987-05-01 |
| EP0239983A2 (en) | 1987-10-07 |
| NO175513C (en) | 1994-10-26 |
| EP0239983B1 (en) | 1991-11-21 |
| EP0239983A3 (en) | 1988-11-30 |
| ES2027246T3 (en) | 1992-06-01 |
| DE3774601D1 (en) | 1992-01-02 |
| DK162887A (en) | 1987-10-02 |
| ZA872326B (en) | 1988-12-28 |
| DE3610878A1 (en) | 1987-10-08 |
| MX5814A (en) | 1993-10-01 |
| NO175513B (en) | 1994-07-18 |
| NO871350D0 (en) | 1987-03-31 |
| NO871350L (en) | 1987-10-02 |
| IL82065A0 (en) | 1987-10-20 |
| KR950002881B1 (en) | 1995-03-28 |
| DK162887D0 (en) | 1987-03-31 |
| NZ219823A (en) | 1990-05-28 |
| FI871378A (en) | 1987-10-02 |
| ATE69547T1 (en) | 1991-12-15 |
| PT84604B (en) | 1989-11-30 |
| FI94313C (en) | 1995-08-25 |
| AU600712B2 (en) | 1990-08-23 |
| AU7095687A (en) | 1987-10-08 |
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| Date | Code | Title | Description |
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| MKLA | Lapsed |