WO1995002396A1 - Preparation de petites spheres encapsulees dans une matrice - Google Patents

Preparation de petites spheres encapsulees dans une matrice Download PDF

Info

Publication number
WO1995002396A1
WO1995002396A1 PCT/US1994/007817 US9407817W WO9502396A1 WO 1995002396 A1 WO1995002396 A1 WO 1995002396A1 US 9407817 W US9407817 W US 9407817W WO 9502396 A1 WO9502396 A1 WO 9502396A1
Authority
WO
WIPO (PCT)
Prior art keywords
matrix
beadlets
preparation
particles
wax
Prior art date
Application number
PCT/US1994/007817
Other languages
English (en)
Inventor
Prasad S. Adusumilli
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP7504669A priority Critical patent/JPH09500135A/ja
Priority to CA002167050A priority patent/CA2167050A1/fr
Priority to BR9407335A priority patent/BR9407335A/pt
Priority to AU72580/94A priority patent/AU684528B2/en
Priority to KR1019960700229A priority patent/KR960703572A/ko
Priority to EP94922131A priority patent/EP0785777A1/fr
Priority to SK33-96A priority patent/SK3396A3/sk
Publication of WO1995002396A1 publication Critical patent/WO1995002396A1/fr
Priority to NO960098A priority patent/NO960098L/no
Priority to FI960133A priority patent/FI960133A/fi

Links

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
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • This invention relates to solid, transparent or semi-transparent, pharmaceutically acceptable preparations (troches, lozenges) comprising one or more matrix-forming materials in which are entrapped small particles which contain at least one beneficial agent.
  • This presentation interdicts tampering with the particles and their active agent and makes the preparations more tamper evident and tamper proof.
  • Troches also known as lozenges or pastilles, are disc-shaped solids containing a medical agent in a suitably flavored base.
  • the base may be a hard sugar candy, glycerinated gelatin or the combination of sugar with sufficient mucilage to provide stability to a shape or form. These products are placed in the mouth where they slowly dissolve, liberating the active ingredient.
  • Troches can be prepared extemporaneously by a trained and licensed formulator.
  • a classic method is to add water to a mixture of powdered drug, sugar and a gum until a pliable mass is obtained. This mass is shaped into roll and pieces are cut from this cane.
  • Heat-stable compounds can be formulated into a hard candy base; such preparations are usually called lozenges.
  • a sugar syrup, with or without a binder is concentrated over heat until it becomes a pliable mass at which point the active is added and the mixture is kneaded while warm to form a homogeneous mass. This warm mass is then processed through a mold to give shape to product which is cooled thus forming the hard candy. Compression-based manufacturing has been used to prepare troches containing heat-labile ingredients.
  • This invention provides an advance in this art by providing a troche-like preparation as a carrier means for particulates, particularly beadlets, whereby the native condition of the beadlets can be observed through the matrix-forming material, in addition to the fact the integrity of the troche-like product can be observed at any point after manufacture or packaging.
  • This invention comprises a pharmaceutically acceptable preparation comprising at least one pharmaceutically acceptable transparent or semi-transparent solid matrix-forming material in which are entrapped small particles which contain at least one beneficial agent.
  • this invention relates to a process for manufacturing these products using injection molding.
  • the finished product is a pharmaceutical preparation comprising some type of matrix- forming, edible material in which are entrapped small particles which comprise or contain an active agent
  • the matrix-forming material is some edible material which is a solid at ambient temperature and is transparent, or semi-transparent to a degree that is no greater than what allows the user to view some or all of the entrapped particles when viewed under normal lighting conditions by the naked eye.
  • Lozenge and troche preparations are illustrations of preparations within the scope of this invention. The compositional make-up of troche and lozenge preparations can be found in such texts as Remington's Pharmaceutical Sciences. 18th Ed., Mack Publishing Co., Easton, PA, USA, pp 1644-1665 (1990) and Sugar Confectionery Manufacture.
  • the matrix may be formed using one compound, for example a wax or a sugar or a mixture of materials can be employed. Mixtures may comprise two or more materials from the same class of compounds, such as mixed sugars, or may be a mixture of compounds from two or more classes such as a sugar, a wax and a polyol.
  • mixtures may be used in a way that causes them to retain their original identity, or they may be transformed during the manufacturing process to a second form representing a combining of subunits into a different chemical entity such as happens when polymerization or cross-linking occurs.
  • Preferred matrix-forming materials are sugars and edible waxes.
  • Sugars such as sucrose, dextrose, fructose, sorbitol, lycasin and other simple and complex carbohydrates which can be used to form lozenges are preferred.
  • Waxes such as white wax, gelucires, carnauba wax, hydrogenated vegetable oils, Labrafils, Compritol 888 ATO, Precirol, polyethylene glycols, bees wax, paraffins, microcrystalline wax, acetylated monoglycerides, cetyl alcohol, and glyceryl monostearate.
  • White wax is a particularly prefe ⁇ ed matrix- forming agent for use in this invention.
  • Non-disintegrating matrices can be formed using hydrophoibic matrix- forming materials described above.
  • Disintegrating matrices can be formed using a combination of hydrophilic and hydrophobic matrix forming materials; these are represented by the list of materials given above. The ratio of hydrophobic to hydrophilic materials can be adjusted to accomplish a desired disintegration time.
  • disintegrants such as Ad-Di-Sol, Explotab, Pregelatinized starches, crospovidone NF and other materials known to the formulation art can be incorporated into the matrix as fine powder or beadlets.
  • any sort of particle can be used in this formulation, so long as it contains or comprises one or more beneficial agents, is stable in the matrix-forming material during manufacturing and storage, and has sufficient size and definition in terms of shape and color so that it is visible in the matrix. Colored beadlets, as described below are most preferred.
  • beneficial agent means any compound or material which acts on a mammal in one fashion or another when consumed for its intended use in the manner prescribed.
  • a drug is a beneficial agent for the purposes of this definition.
  • other compounds which can have a subjective or objective beneficial effect on the user and which are to be included within the meaning of this term.
  • an antacid or anti-gas agent can have a beneficial effect when used to treat indigestion.
  • a breath freshener provides an objective and a subjective beneficial effect to many people.
  • Nutritional agents such as vitamins, minerals, or amino acid supplements are beneficial to those needing to supplement their diet. Flavors and sweeteners provide a subjective benefit and a source of energy as well, and are also included.
  • Drugs and drug delivery are of greatest interest herein.
  • the word "drug” is used in its broadest sense and includes any agent which exhibits a pharmacological effect on the user and which can be administered via SGC technology utilizing particles as described herein. Any solid or liquid form of a drug can be used provided it can be manufactured into a particulate, as is true for any compound which constitutes a beneficial agent for the purposes of this invention. Both fat soluble and water soluble drugs may be used. Drugs for treating cough, cold, and allergy symptoms are of most interest.
  • Phenylpropanolamine hydrochloride, caramiphen edisylate, acetaminophen, aspirin or another non-steroidal anti-inflammatory, pseudoephrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate are most preferred.
  • Beadlet size can vary in any given capsule. Preferred beadlets will have a diameter in the range of about 149 to 1190 microns. The most preferred particle size is between about 420 and 840 microns microns (about 20-40 mesh). Particle size can vary in a given preparation or particles of different narrow ranges can be confected and these final products mixed to provide a choice of preparations with different particle sizes.
  • Particles can be comprised of pure agent or, as will more often be the case, the agent can be coated with a protective layer which may or may not affect how fast the particle dissolves and releases the active ingredient.
  • Creating particles of pure agent is mostly a matter of shaping the raw material by some means, usually a mechanical means.
  • a coating of some sort may be added to protect the neat compound. More often than not, one will want to coat the particles for both functional and aesthetic reasons.
  • Pan coating for example, is a well established technology that provides a basic pellet.
  • a more sophisticated approach is to create a core and then to add one or more layers of a coating to the core.
  • any particles with different coating thicknesses are loaded into one capsule, drug can be delivered over an extended period to time.
  • This technology was pioneered by R. H. Blythe in U.S. patent 2,738,303. He describes there a therapeutic preparation in unit dosage form prepared from non-pariel seeds (sugar pellets), screened, placed in a coating pan, wetted with syrup, then treated with a 80:20 mixture of dextro- amphetamine sulfate and calcium sulfate dihydrate, then dried.
  • Particles can be prepared in a single color, or in different colors if desired. Dyes and lakes of any sort may be used so long as they are not toxic or do not have an untoward or deleterious effect on the user. For example blue particle could be prepared for use with a translucent white wax lozenge. Or red, white and blue beadlets could be incorporated into a sorbitol base to provide an aesthetically pleasing lozenge. Particle stability, as compared with stability of the active agent, is another factor which must be taken into consideration. Particles must remain chemically and physically stable under the conditions used to manufacture troches. Furthermore, particle and matrix must not undergo some kind of chemical or physical interaction once manufactured. It is not possible to identify or define all of the conditions or combinations which could lead to particle-matrix interactions. However, particulates coatings known to be soluble in sorbitol or corn syrup should not be used to formulate coated beads where such sugars are the intended matrix-forming agent.
  • Stability of the beneficial agent is a consideration as well, just as it is with any formulation, not just these preparations. There is no single recipe for formulating a product which will not degrade chemically. Each formulation must be addressed on a case-by-case basis; this is within the skill of one trained in the formulation arts.
  • Lozenges for example, are commonly manufactured by preparing a candy base by combining ingredients and cooking the mix, with or with out stirring, to create the stock from which the lozenge will be prepared. Then a portion of this mix which is held at an elevated temperature to keep it liquid is used as a diluent; particles are added to the liquid mix with stirring to create a dispersion. This material is poured into molds, cooled and packaged. Alternatively, products may be made by injection molding techniques. This approach is particularly useful where waxes are used as the matrix-forming agent. A heated mixture of wax and particles is passed through an injection molding apparatus in such as manner as to fill mold and allow for cooling of the product during the manufacturing cycle.
  • a premixed stream of room temperature material is processed under pressure into molds to eliminate the need for a cooling step.
  • a feed stock of matrix-forming material can be mixed with a feed-stock stream of particles, passed through a mixing device and injected into a mold to form the final product.
  • Other injection molding processes are considered to be within the purview of this invention.
  • Finished product may be packaged without any special handling precautions.
  • the usual considerations such as the need to exclude moisture or ultraviolet light should be taken into consideration.
  • the invention can be practiced within the context of packaging the product in opaque jar or overwrap.
  • Any form or shape can be used in this invention.
  • Troches or lozenges may be uniform in shape such as is the case for an oval, square, rectangular, or have multiple sided presentation.
  • Geometric forms can be used. Shapes representing persons or things, either real or imagined can be prepared, especially when injection molding techniques are used. Shape and form are limited only by the imagination of the practitioner. The following examples are provided to illustrate the invention. They are not to be read as limiting the invention in any manner.
  • Example 1 Preparation of Wax Matrix Caplets Containing Beadlets A required amount of white wax was taken into a glass beaker and heated in an oil bath until the wax melted using a hot plate. Beadlets obtained from Central Pharmaceuticals, Inc. Seymour, Indiana, were poured into the molten wax and stirred with a spatula to obtain a homogenous suspension. The molten wax/bead suspension was carefully poured into molds and allowed to cool and form hard caplets. These caplets were then pushed out of the molds.
  • the active ingredients in the beadlets were chlorpheneramine maleate 12.0 mg and phenylpropanolamine HC175.0 mg. These beadlets were differentially coated so that some beadlets would release the actives immediately, and others would release their active ingredients at several time points over a 12 hour period.
  • the active ingredients in the beadlets were chlorpheneramine maleate 12.0 mg and phenylpropanolamine HC175.0 mg. These beadlets were differentially coated so that some beadlets would release the actives immediately, and others would release their active ingredients at several time points over a 12 hour period.

Abstract

L'invention se rapporte à une préparation pharmaceutiquement acceptable comprenant une ou plusieurs substances constituant une matrice, dans lesquelles sont encapsulées des particules contenant au moins un agent thérapeutique.
PCT/US1994/007817 1993-07-12 1994-07-12 Preparation de petites spheres encapsulees dans une matrice WO1995002396A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP7504669A JPH09500135A (ja) 1993-07-12 1994-07-12 ビーズレットをトラップするマトリックス製剤
CA002167050A CA2167050A1 (fr) 1993-07-12 1994-07-12 Preparation de granules pieges dans une matrice
BR9407335A BR9407335A (pt) 1994-07-12 1994-07-12 Grânulos medicinais contidos em matriz
AU72580/94A AU684528B2 (en) 1993-07-12 1994-07-12 Matrix-entrapped beadlet preparation
KR1019960700229A KR960703572A (ko) 1993-07-12 1994-07-12 기질-포집 비이드 제제(matrix-entrapped beadlet preparation)
EP94922131A EP0785777A1 (fr) 1993-07-12 1994-07-12 Preparation de petites spheres encapsulees dans une matrice
SK33-96A SK3396A3 (en) 1993-07-12 1994-07-12 Pharmaceutically acceptable composition and preparation method thereof
NO960098A NO960098L (no) 1993-07-12 1996-01-09 Preparat i form av matriks-innesluttede små perler
FI960133A FI960133A (fi) 1993-07-12 1996-01-11 Matriisiin sidottu partikkelivalmiste

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9038793A 1993-07-12 1993-07-12
US08/090,387 1993-07-12

Publications (1)

Publication Number Publication Date
WO1995002396A1 true WO1995002396A1 (fr) 1995-01-26

Family

ID=22222565

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/007817 WO1995002396A1 (fr) 1993-07-12 1994-07-12 Preparation de petites spheres encapsulees dans une matrice

Country Status (15)

Country Link
EP (1) EP0785777A1 (fr)
JP (1) JPH09500135A (fr)
KR (1) KR960703572A (fr)
CN (1) CN1130867A (fr)
AU (1) AU684528B2 (fr)
CA (1) CA2167050A1 (fr)
CZ (1) CZ6696A3 (fr)
FI (1) FI960133A (fr)
HU (1) HUT73666A (fr)
NO (1) NO960098L (fr)
NZ (1) NZ269103A (fr)
PL (1) PL312503A1 (fr)
SK (1) SK3396A3 (fr)
WO (1) WO1995002396A1 (fr)
ZA (1) ZA944949B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007600A1 (fr) 1995-08-18 1997-02-27 Nokia Mobile Phones Limited Procede d'ajustement de la puissance d'emission lors de l'etablissement d'une communication, et systeme de radiocommunications cellulaire
WO2003026614A1 (fr) * 2001-09-28 2003-04-03 Mcneil-Ppc, Inc. Forme de dosage contenant une composition de confiserie
WO2003089007A1 (fr) * 2002-04-22 2003-10-30 Adcock Ingram Intellectual Property (Proprietary) Limited Compositions pharmaceutiques comprenant un decongestionnant et d'autres ingredients actifs pour traiter la toux et la grippe
US6837696B2 (en) 2001-09-28 2005-01-04 Mcneil-Ppc, Inc. Apparatus for manufacturing dosage forms
US7122143B2 (en) 2001-09-28 2006-10-17 Mcneil-Ppc, Inc. Methods for manufacturing dosage forms
US7807197B2 (en) 2002-09-28 2010-10-05 Mcneil-Ppc, Inc. Composite dosage forms having an inlaid portion
US7838026B2 (en) 2001-09-28 2010-11-23 Mcneil-Ppc, Inc. Burst-release polymer composition and dosage forms comprising the same
US8673352B2 (en) 2005-04-15 2014-03-18 Mcneil-Ppc, Inc. Modified release dosage form

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649043A (en) * 1982-03-22 1987-03-10 Alza Corporation Drug delivery system for delivering a plurality of tiny pills in the gastrointestinal tract

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US4113509A (en) * 1975-05-14 1978-09-12 Cpc International Inc. Enzymatically produced maltose-maltotriose starch hydrolysate
US4894233A (en) * 1984-10-05 1990-01-16 Sharma Shri C Novel drug delivery system for decongestants
US4820523A (en) * 1986-04-15 1989-04-11 Warner-Lambert Company Pharmaceutical composition
US4996047A (en) * 1988-11-02 1991-02-26 Richardson-Vicks, Inc. Sustained release drug-resin complexes
US4963359A (en) * 1989-01-30 1990-10-16 Plough, Inc. Non-cariogenic confections
DE69004927T2 (de) * 1989-05-01 1994-06-30 Baxter Int Zusammensetzung eines heilmittels und verfahren zur verabreichung bei einer kontrollierten lösungsgeschwindigkeit.
EP0418596A3 (en) * 1989-09-21 1991-10-23 American Cyanamid Company Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649043A (en) * 1982-03-22 1987-03-10 Alza Corporation Drug delivery system for delivering a plurality of tiny pills in the gastrointestinal tract

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007600A1 (fr) 1995-08-18 1997-02-27 Nokia Mobile Phones Limited Procede d'ajustement de la puissance d'emission lors de l'etablissement d'une communication, et systeme de radiocommunications cellulaire
US7838026B2 (en) 2001-09-28 2010-11-23 Mcneil-Ppc, Inc. Burst-release polymer composition and dosage forms comprising the same
US6837696B2 (en) 2001-09-28 2005-01-04 Mcneil-Ppc, Inc. Apparatus for manufacturing dosage forms
US7122143B2 (en) 2001-09-28 2006-10-17 Mcneil-Ppc, Inc. Methods for manufacturing dosage forms
WO2003026614A1 (fr) * 2001-09-28 2003-04-03 Mcneil-Ppc, Inc. Forme de dosage contenant une composition de confiserie
US7968120B2 (en) 2001-09-28 2011-06-28 Mcneil-Ppc, Inc. Modified release dosage forms
US7972624B2 (en) * 2001-09-28 2011-07-05 Shun-Por Li Method of manufacturing modified release dosage forms
US8114328B2 (en) 2001-09-28 2012-02-14 Mcneil-Ppc, Inc. Method of coating a dosage form comprising a first medicant
US8545887B2 (en) 2001-09-28 2013-10-01 Mcneil-Ppc, Inc. Modified release dosage forms
US8673190B2 (en) 2001-09-28 2014-03-18 Mcneil-Ppc, Inc. Method for manufacturing dosage forms
WO2003089007A1 (fr) * 2002-04-22 2003-10-30 Adcock Ingram Intellectual Property (Proprietary) Limited Compositions pharmaceutiques comprenant un decongestionnant et d'autres ingredients actifs pour traiter la toux et la grippe
US7807197B2 (en) 2002-09-28 2010-10-05 Mcneil-Ppc, Inc. Composite dosage forms having an inlaid portion
US8673352B2 (en) 2005-04-15 2014-03-18 Mcneil-Ppc, Inc. Modified release dosage form

Also Published As

Publication number Publication date
KR960703572A (ko) 1996-08-31
FI960133A (fi) 1996-03-11
AU7258094A (en) 1995-02-13
PL312503A1 (en) 1996-04-29
NO960098D0 (no) 1996-01-09
CN1130867A (zh) 1996-09-11
HU9600048D0 (en) 1996-03-28
HUT73666A (en) 1996-09-30
NO960098L (no) 1996-02-20
SK3396A3 (en) 1997-04-09
FI960133A0 (fi) 1996-01-11
ZA944949B (en) 1995-04-05
EP0785777A1 (fr) 1997-07-30
JPH09500135A (ja) 1997-01-07
AU684528B2 (en) 1997-12-18
EP0785777A4 (fr) 1997-07-30
CA2167050A1 (fr) 1995-01-26
CZ6696A3 (en) 1996-06-12
NZ269103A (en) 1997-09-22

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