EP0721333A1 - Particules encapsulees dans la gelatine formant une enveloppe souple - Google Patents

Particules encapsulees dans la gelatine formant une enveloppe souple

Info

Publication number
EP0721333A1
EP0721333A1 EP94922103A EP94922103A EP0721333A1 EP 0721333 A1 EP0721333 A1 EP 0721333A1 EP 94922103 A EP94922103 A EP 94922103A EP 94922103 A EP94922103 A EP 94922103A EP 0721333 A1 EP0721333 A1 EP 0721333A1
Authority
EP
European Patent Office
Prior art keywords
capsule
beadlets
soft
gelatin
filled
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.)
Withdrawn
Application number
EP94922103A
Other languages
German (de)
English (en)
Other versions
EP0721333A4 (fr
Inventor
Prasad S. Adusumilli
Philip E. West
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 Corp filed Critical SmithKline Beecham Corp
Publication of EP0721333A1 publication Critical patent/EP0721333A1/fr
Publication of EP0721333A4 publication Critical patent/EP0721333A4/fr
Withdrawn legal-status Critical Current

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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • This invention relates to a soft-shelled gelatin capsule filled with beadlets which contain at least one beneficial agent. This presentation makes the capsule more tamper evident
  • Capsules can be prepared in many forms, for example these capsules are produced commercially in round, oval, oblong, tube and suppository form. Commercial processes usually produce the capsule with a seam transcribing the long axis of the capsule. In oral dosage forms this seam is produced by a heat sealing process in such as way as to insure this seam is the point of opening and that this occurs rapidly in the stomach, i.e. in less than five minutes.
  • Capsules for suppository use usually are formulated so that this seam breaks down in the presence of the moisture present in the body cavity. This form of drug delivery and the associated technology for manufacturing them is well documented and available from research and commerc l sources.
  • This invention involves a modification to the soft gelatin capsule technology so as to be able to incorporate beadlets directly into the soft capsule without degrading or deforming the beadlets.
  • This invention comprises a partially or wholly transparent soft gelatin capsule preparation wherein the internal volume is filled with beadlets or beadlets in a hard-shelled gelatin skin wherein the beadlets contain a beneficial agent.
  • the finished product consists of a soft gelatin shell which has been filled with beadlets which contain at least one beneficial agent where the gelatin coating is transparent over-all or over a major portion of the product
  • the finished capsule will be sufficiently translucent so as to allow the particles to be seen through the soft gelatin wall under normal lighting conditions no matter how the capsule is oriented.
  • all of the soft gel capsule wall will be translucent.
  • a portion of the soft gel capsule will have a different refractive index or will transmit more light than another portion of the capsule.
  • one portion of the capsule will be opaque while the other portion will be transparent.
  • a capsule where one-half of an elliptical capsule is opaque, either the as measured by its long axis or its short axis.
  • a preferred form of this capsule will be one where the capsule if filled with beadlets and all parts of the soft gel wall are transparent to essentially the same extent.
  • Another preferred variation is one in which beadlets have been filled into a hard-shelled gelatin capsule and are then coated with soft gelatin to provide a transparent preparation where the hard- shelled capsule and its contents are visible to the naked eye under normal lighting conditions.
  • the soft gelatin wall-forming materials any materials known to the art may be used to form the shell.
  • Such materials may contain cross-linking or polymerizing agents, stabilizers, antioxidants, light absorbing agents for protecting light-sensitive fills, preservatives and the like.
  • Soft gelatin capsule wall-forming materials are well documented in the literature and are well known to manufacturers and technicians alike.
  • formulating and mixing ingredients in preparation for manufacturing SGCs may follow any route or utilize any technique known to the art.
  • beadlet can be used in this formulation, so long as it contains or comprises at least one beneficial agent, is stable during the capsule-manufacturing process and during storage, and is visible to the naked eye.
  • 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 fresherner 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 paniculate, 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. They include antihistamines; drugs for treating inflammation, pain and pyrexia; nasal decongestants; expectorants; sedatives as used in cough and cold remedies, and the like.
  • Phenylpropanolamine hydrochloride, caramiphen edisylate, acetaminophen, aspirin or another non-steroidal anti-inflammatory, pseudoephrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate are most preferred.
  • beadlets and stability are the primary concerns. So far as size is concerned, the principal consideration will be that of creating a particle of a size such that the particles are visible to the naked eye under normal lighting conditions.
  • Preferred beadlets will have a diameter in the range of about 149 to 1190 microns. Beadlet size can vary in any given capsule. The preferred particle size is between about 420 and 840 microns microns (about 20-40 mesh).
  • Beadlets 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 beadlets 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. This process was repeated several times to build up drug on the non-pariel seed; it is treated with talc to create the core pellet.
  • Color variations in the particles can be used to make capsules esthetically more pleasing.
  • Dyes or 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 and do not adversely affect stability of the beneficial agent.
  • Beadlet stability is another factor which must be taken into consideration when formulating beadlets. Beadlets must remain chemically inert when in contact with the gelatin wall-forming materials and whatever materials may leach out of the wall-forming materials. It is not possible to identify all of the combinations which could lead to particle-carrier interactions. Beadlet coatings known to be soluble in soft gelatin wall-forming materials should not be used to formulate coated beads if that vehicle is the vehicle of choice. Also, it should be kept in mind that gelatin materials used to make SGC contain substantial amounts of water which may migrate into the spaces between the beadlets or be absorbed by the beadlets and have a deleterious effect on the particulates.
  • Stability of the beneficial agent is a consideration as well, just as it is with any formulation, not just these preparations.
  • Each formulation must be addressed on a case-by-case basis; this is within the skill of one trained in the formulation arts. Beadlets which do not require a sustained release coat will implicitly require a suitable coat to maintain stability within the finished product
  • An alternative is to first fill the beadlets into a hard-shelled gelatin capsule then coat this capsule with a soft gelatin material which dries to a soft film; in other words coats the hard shelled gelatin capsule with a soft gelatin shell.
  • This can be done by first preparing the hard-shelled gelatin capsule preparation where the fill is beadlets, then passing the finished hard gel capsules through a manufacturing process which coats the capsule with soft gelatin. This provides a second seal for the hard shelled capsule and renders it tamper resistant and tamper evident
  • Examples of useful manufacturing techniques which can be modified to accommodate this invention are the plate process, the rotary-die process pioneered by R. P.
  • Capsules may be oval, square, rectangular, have a dumbbell shape, look like an hour-glass, or have multiple sides, e.g. octagonal, hexagonal, pentagonal or the like.
  • the following examples are provided to illustrate the invention. They are not to be read as limiting the invention in any manner.
  • Example 1 Capsule Preparation
  • Large soft gelatin capsules containing vitamin E were purchased from the local pharmacy store. Individual capsules were slit on one end such that there was enough opening to empty the contents. Contents of these capsules were squeezed out through the opening. These empty capsules were then washed in absolute ethanol several times, such that all traces of previous con * , nt ⁇ were removed and dried at room temperature for a few hours.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Cosmetics (AREA)

Abstract

L'invention se rapporte à une capsule de gélatine à enveloppe souple remplie de petites sphères contenant un agent médicamenteux. Cette présentation rend la capsule plus inviolable.
EP94922103A 1993-07-09 1994-07-08 Particules encapsulees dans la gelatine formant une enveloppe souple Withdrawn EP0721333A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8936193A 1993-07-09 1993-07-09
US89361 1993-07-09
PCT/US1994/007629 WO1995001787A1 (fr) 1993-07-09 1994-07-08 Particules encapsulees dans la gelatine formant une enveloppe souple

Publications (2)

Publication Number Publication Date
EP0721333A1 true EP0721333A1 (fr) 1996-07-17
EP0721333A4 EP0721333A4 (fr) 1997-06-04

Family

ID=22217237

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94922103A Withdrawn EP0721333A4 (fr) 1993-07-09 1994-07-08 Particules encapsulees dans la gelatine formant une enveloppe souple

Country Status (17)

Country Link
EP (1) EP0721333A4 (fr)
JP (1) JPH08511268A (fr)
CN (1) CN1130869A (fr)
AU (1) AU687420B2 (fr)
BR (1) BR9407193A (fr)
CA (1) CA2166768A1 (fr)
CZ (1) CZ6596A3 (fr)
FI (1) FI960099A (fr)
HU (1) HUT74640A (fr)
MY (1) MY111346A (fr)
NO (1) NO960097L (fr)
NZ (1) NZ269094A (fr)
PL (1) PL312987A1 (fr)
RU (1) RU2135164C1 (fr)
SK (1) SK3496A3 (fr)
WO (1) WO1995001787A1 (fr)
ZA (1) ZA944878B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5624681A (en) * 1995-04-26 1997-04-29 R. P. Scherer Corporation Tamper evident pharmaceutical dosage form
GB9605948D0 (en) * 1996-03-21 1996-05-22 Smithkline Beecham Plc Novel formulations
AUPP022297A0 (en) 1997-11-06 1997-11-27 R.P. Scherer Holdings Pty Ltd Vitamin coating
DE19820529A1 (de) * 1998-05-08 1999-11-11 Lohmann Therapie Syst Lts Wirkstoff enthaltende orale und mucosale Zubereitung mit steuerbarer Wirkstofffreisetzung und ihre Verwendung

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000125A1 (fr) * 1993-06-18 1995-01-05 Smithkline Beecham Corporation Particules encapsulees dans une enveloppe souple en gelatine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4434153A (en) * 1982-03-22 1984-02-28 Alza Corporation Drug delivery system comprising a reservoir containing a plurality of tiny pills
US4665098A (en) * 1985-03-28 1987-05-12 Mcneilab, Inc. Pharmaceutical composition of N-(4-hydroxyphenyl) retinamide having increased bioavailability
US4961932A (en) * 1987-10-26 1990-10-09 Alza Corporation Plurality of tiny pills in liquid dosage form
WO1994008576A1 (fr) * 1992-10-16 1994-04-28 Glaxo Group Limited Compositions a base de ranitidine masquant le gout de celle-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000125A1 (fr) * 1993-06-18 1995-01-05 Smithkline Beecham Corporation Particules encapsulees dans une enveloppe souple en gelatine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9501787A1 *

Also Published As

Publication number Publication date
ZA944878B (en) 1995-04-21
FI960099A (fi) 1996-03-08
JPH08511268A (ja) 1996-11-26
EP0721333A4 (fr) 1997-06-04
HU9600049D0 (en) 1996-03-28
BR9407193A (pt) 1996-09-10
NZ269094A (en) 1997-09-22
AU687420B2 (en) 1998-02-26
SK3496A3 (en) 1997-04-09
FI960099A0 (fi) 1996-01-09
NO960097L (no) 1996-02-13
AU7256294A (en) 1995-02-06
CA2166768A1 (fr) 1995-01-19
PL312987A1 (en) 1996-05-27
CZ6596A3 (en) 1996-06-12
CN1130869A (zh) 1996-09-11
HUT74640A (en) 1997-01-28
NO960097D0 (no) 1996-01-09
WO1995001787A1 (fr) 1995-01-19
MY111346A (en) 1999-11-30
RU2135164C1 (ru) 1999-08-27

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