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WO1999022768A1 - Composition a liberation lente comprenant des gels a gomme gellane - Google Patents

Composition a liberation lente comprenant des gels a gomme gellane Download PDF

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Publication number
WO1999022768A1
WO1999022768A1 PCT/US1998/023093 US9823093W WO9922768A1 WO 1999022768 A1 WO1999022768 A1 WO 1999022768A1 US 9823093 W US9823093 W US 9823093W WO 9922768 A1 WO9922768 A1 WO 9922768A1
Authority
WO
WIPO (PCT)
Prior art keywords
release
drug
gellan gum
gum
controlled release
Prior art date
Application number
PCT/US1998/023093
Other languages
English (en)
Inventor
Thierry Nivaggioli
Original Assignee
Monsanto Company
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 Monsanto Company filed Critical Monsanto Company
Priority to EP98956386A priority Critical patent/EP1027072A1/fr
Priority to AU12921/99A priority patent/AU744328B2/en
Priority to JP2000518698A priority patent/JP2004500305A/ja
Priority to CA002308291A priority patent/CA2308291A1/fr
Publication of WO1999022768A1 publication Critical patent/WO1999022768A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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

  • the present invention relates to a composition and method for the effective controlled timed release of various molecular weight biologically active molecules ranging from small molecular weight vitamins to large proteins to an intended recipient such as a human or animal in an therapeutically effective manner and amount employing gellan gum.
  • Encapsulation of ingredients in gels is known.
  • Japanese Patent No. 62125850 discloses encapsulation of ingredients, such as food, oils, medicines and the like, within beads of gellan gum.
  • This published patent application reports that in an example, a salad oil emulsion was added as 0.5ml size drops to a 1% gellan gum solution.
  • This publication reports that resulting beads had a 0.35mm thick skin and contained 0.3ml of oil in each sphere.
  • GB Patent No. 2219803 discloses a gelling composition which comprises a blend of gellan, kappa-carrageenan and mannan. This gelling composition is said to be useful as a gelling matrix in food products such as pet foods and the like.
  • Japanese Patent No. 63267361 discloses a gel which is said to contain fragrances, microbicides, insecticides, and the like, in addition to a gelation agent selected from gellan gum, and its combination with carrageenan, gelatin, agar, locust bean, gum, xanthan gum, carboxymethyl cellulose and the like.
  • the present invention provides a composition and a method whereby gellan gum gels can be used effectively to release biologically active molecules in an effective controlled release manner over time.
  • a method is also provided for setting, adjusting and regulating the release characteristics for an intended recipient and user such as a human or an animal.
  • a therapeutic effective amount of active ingredient is delivered to the recipient by this invention.
  • a gellan gum is provided with an effective pore size range that can be easily modified to affect the release characteristics of a biologically active molecule to its intended recipient such as a human or an animal.
  • the present invention enables a "tunable" release of biologically active molecules to the intended target over, during and after a desired time.
  • Such tuning can be achieved in several ways including by varying gum concentration, the nature and concentration of gelling cations, and by incotporating other polymers in the gel network.
  • a polymer of choice to be added to gellan gum gel is xantban gum. Increasing the concentration of xanthan gum in the gel increases the viscosity in the gel and reduce its effective pore size.
  • a useful property of gellan gum for the present invention is its ability to gel with most cations, including counter ions of the biologically active molecule to be incorporated into the gel.
  • the gel phase employed in this invention comprises a gellan gum.
  • Gellan Gum is a naturally occuring polysaccharide that is produced by inoculating a carefully formulated fermentation medium with the microorganism Sphingomonas elodea (ATTC 31461).
  • Gellan gum is available in clarified form KELOGEL® for foods and industrial products and a clarified form GELRITE ® from Monsanto Company, St. Louis, Missouri, for microbiological media, plant tiessue culture and pharmaceutical applications.
  • the gelling mechanism of Gellan Gum is based on cation inducted macromolecular chain reorganization.
  • Gellan gum includes nonclarif ⁇ ed, clarified, and partially clarified native, deacylated and partial deacylated forms as well as mixtures thereof and the like.
  • a process for the preparation of gels useful herein comprises admixing water with gellan gum to a concentration from about 0.1% to about 5% by weight to form a gum containing composition, with or without sequestraut, optionally with other polymers, and maintaining said gum composition at a temperature sufficiently warm to maintain full hydration of said gum such that gelation will occur upon subsequent cooling.
  • a biologically-active ingredient may then be admixed with the warm solution along with optionally admixing solubilizing and suspending aids. Further optionally admixing therewith includes cations. Cooling the warm solution containing said biologically active ingredient to a temperature in the range sufficient to induce gelation then follows. The biologically active ingredient is thus within the gelled gum.
  • the gellan gum be present in the gelled phase in an amount of about 0.1 to about 5% by weight, based on the weight of the gelling agent in water, for example, about 0.25 to about 2.5% by weight although greater or lesser amounts may be employed if desired.
  • the gelled phase may also optionally contain a preservative.
  • a preferred preservative is n-propyl p-hydroxybenzoate and the like.
  • the preservative is suitably employed in a minor amount, such as not greater than about 0.2% by weight of the gelled phase although greater or lesser amounts may be employed if desired.
  • the gelled phase may further contain a biocide, typically present in an amount of about 0.05% to about 2.5% by weight based on the weight of the gelled phase although greater or lesser amounts may be employed if desired.
  • a biocide typically present in an amount of about 0.05% to about 2.5% by weight based on the weight of the gelled phase although greater or lesser amounts may be employed if desired.
  • the gellan gum may typically be gelled by a suitable cation such as calcium, magnesium, mixtures thereof and the like.
  • a particularly attractive method of inducing gelation is to use the counter ion of biologically active molecule(s) to be incorporated into the gel.
  • the form and texture of the gel will depend on the desired application. For example, to be used as an oral (intact) delivery system care should be taken to obtain a gel hard enough to be handled easily by hand without breaking or damage to the gel. If the gel needs to be mixed with food, a softer, easier to break gel structure maybe desirable. Such change of texture can easily be adjusted by the person skilled in the art by varying gum and cation concentration and other optional additives after reading this specification.
  • these illustrative cations could be suitably provided by salts such as calcium chloride, magnesium chloride, calcium sulphate, magnesium sulphate, mixtures thereof and the like.
  • Other suitable cations may be employed if desired, including that of the biologically active molecule(s).
  • the gelling solution remains substantially free of multivalent ions, such as calcium, magnesium or the like.
  • multivalent ions such as calcium, magnesium or the like.
  • an object of the present invention is to contain within a gel having effective release properties a biologically active ingredient for its subsequent controlled release from the gel.
  • the active ingredients comprise small molecules or larger proteins whose release characteristics may be different and can be tuned in different ways for effective release to a human or animal as has been discovered in this invention.
  • biologically active molecules includes without limitation, for small species, ascorbic acid (vitamin C), sodium naproxen, sodium salicylate, ibuprofen and for larger proteins, insulin, myoglobin, bovine somatotropin, and albumin, mixtures thereof and the like.
  • vitamin C ascorbic acid
  • sodium naproxen sodium naproxen
  • sodium salicylate sodium salicylate
  • ibuprofen and for larger proteins
  • insulin myoglobin
  • bovine somatotropin and albumin
  • Release rates for the active ingredient were obtained using an automated dissolution apparatus with the basket attachments (USP I) at 50 ipm and 37 ⁇ C with 1 liter of solvent. Release media were dionized water for the proteins, 0.1M phosphate buffer for sodium naproxen, simulated gastric fluid (SGF) for vitamin C and sodium salicylate, and simulated intestinal fluid (SIF) for Ibuprofen. Samples of the fluid were removed at timed intervals and compared to the appropriate standard solution on a UV spectrophotometer. Typical release curves are presented in Figures 1 to 9 attached.
  • Figure 1 Release of various actives from.0.5% GELRITE gels (6 mM Ca). In all cases, active dose: 10 mg mL. Average of 3 different gels for each curve.
  • Figure 3 Effect of GELRITE (GR) concentration on the release of Myoglobin (active dose: 10 mg mL) from gels (6 mM Ca). USP 50 RPM, 37°C in deionised water. Average of 3 gels for each curve.
  • GR GELRITE
  • Figure 4 Effect of GELRITE (GR) concentration on the release of Albumin (active dose: 10 mg/mL) from gels (6 mM Ca). USP 50 RPM, 37°C in deionized water. Avera e of 3 els for each curve.
  • Figure 5 Effect of active dose on the release of Albumin from 0.5% (6 mM Ca) GELRITE gels. USP 50 RPM, 37 ⁇ C in deionized water. Average of 3 gels for each curve.
  • Figure 7 Effect of active dose on the release of Ibuprofen from 0.75% (No calcium added) GELRITE gels. USP 50 RPM, 37°C in simulated intestinal fluid (pH 6.8).
  • Figure 8 Effect of active dose on the release of sodium salicylate from 0.75% (No calcium added) GELRITE gels. USP 50 RPM, 37°C in simulated gastric fluid (pH 1.2). Average of 3 gels for each curve.
  • Figure 9 Effect of release medium / solubility on the release characteristics of small molecular weight active ingredients from 0.75% (No calcium added) GELRITE gels.
  • Active dose is 150 mg mL in all cases except for Vitamin C which is 100 mg mL. Average of 3 gels for each curve.
  • gum concentration has little effect on the release characteristics. This is depicted in Figure 2. In this case, one can see that increasing gum concentration in the gel from 0.5% to 0.75% (a 50% increase) has no significant effect on the release curves.
  • Gelrite gels would be, but are not limited to, xanthan gum and native gellan gum (high acyl content).
  • Figure 6 shows that for Ibuprofen, almost identical release curves are obtained when increasing loading from 75 mg/mL to 150 mg/mL (an increase of a factor 2). Similarly for sodium salicylate, an increase from 150 mg mL to 250 mg/mL has little effect on release characteristics. This is depicted in Figure 8 and such property can be used to obtain oral dosage forms with release characteristics independent of the dosage strength, this can be attractive to design similar systems for both children and adults.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un système de gomme gellane à libération lente renfermant, sous forme dispersée, un ingrédient bioactif.
PCT/US1998/023093 1997-10-31 1998-10-30 Composition a liberation lente comprenant des gels a gomme gellane WO1999022768A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98956386A EP1027072A1 (fr) 1997-10-31 1998-10-30 Composition a liberation lente comprenant des gels a gomme gellane
AU12921/99A AU744328B2 (en) 1997-10-31 1998-10-30 Controlled release compositions comprising gellan gum gels
JP2000518698A JP2004500305A (ja) 1997-10-31 1998-10-30 ゲランゴムゲルを含む徐放性組成物
CA002308291A CA2308291A1 (fr) 1997-10-31 1998-10-30 Composition a liberation lente comprenant des gels a gomme gellane

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6382297P 1997-10-31 1997-10-31
US60/063,822 1997-10-31

Publications (1)

Publication Number Publication Date
WO1999022768A1 true WO1999022768A1 (fr) 1999-05-14

Family

ID=22051739

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/023093 WO1999022768A1 (fr) 1997-10-31 1998-10-30 Composition a liberation lente comprenant des gels a gomme gellane

Country Status (5)

Country Link
EP (1) EP1027072A1 (fr)
JP (1) JP2004500305A (fr)
AU (1) AU744328B2 (fr)
CA (1) CA2308291A1 (fr)
WO (1) WO1999022768A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1646367A2 (fr) * 2003-07-21 2006-04-19 Bio-Dar Ltd. Formes dosifiees a liberation controlee a base de gomme gellane a administrer par voie orale, une nouvelle technologie pour la retention gastrique
US9132291B2 (en) 2010-10-05 2015-09-15 Dfb Technology, Ltd. Water-in-oil emulsion compositions containing gellan gum for topical delivery of active ingredients to the skin or mucosa
ITUB20156821A1 (it) * 2015-12-09 2017-06-09 Altergon Sa CAPSULE DI GELATINA MOLLE A RILASCIO pH INDIPENDENTE
US9789191B2 (en) 2010-09-13 2017-10-17 Solixa Technologies, Inc. Aqueous drug delivery system

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4531342B2 (ja) 2003-03-17 2010-08-25 株式会社半導体エネルギー研究所 白色有機発光素子および発光装置

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0130689A1 (fr) * 1983-05-31 1985-01-09 Merck & Co. Inc. Gels non chauffés à base de gomme gellan
JPS62125850A (ja) * 1985-11-26 1987-06-08 San Ei Chem Ind Ltd 球状ゲルの製法
JPS63267361A (ja) * 1987-04-24 1988-11-04 San Ei Chem Ind Ltd 賦香等性ゲル状物
GB2219803A (en) * 1988-06-20 1989-12-20 Merck & Co Inc Gellan/K-carrageenan/mannan blends
WO1996003142A1 (fr) * 1994-07-26 1996-02-08 Danbiosyst Uk Limited Composition d'apport de medicament utile pour administrer des agents antiviraux par voie orale
WO1996040069A1 (fr) * 1995-06-07 1996-12-19 Sri International Systeme et procede de production de microparticules chargees de medicaments
JPH10236983A (ja) * 1997-02-25 1998-09-08 Taisho Pharmaceut Co Ltd ゲル状徐放性組成物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0130689A1 (fr) * 1983-05-31 1985-01-09 Merck & Co. Inc. Gels non chauffés à base de gomme gellan
JPS62125850A (ja) * 1985-11-26 1987-06-08 San Ei Chem Ind Ltd 球状ゲルの製法
JPS63267361A (ja) * 1987-04-24 1988-11-04 San Ei Chem Ind Ltd 賦香等性ゲル状物
GB2219803A (en) * 1988-06-20 1989-12-20 Merck & Co Inc Gellan/K-carrageenan/mannan blends
WO1996003142A1 (fr) * 1994-07-26 1996-02-08 Danbiosyst Uk Limited Composition d'apport de medicament utile pour administrer des agents antiviraux par voie orale
WO1996040069A1 (fr) * 1995-06-07 1996-12-19 Sri International Systeme et procede de production de microparticules chargees de medicaments
JPH10236983A (ja) * 1997-02-25 1998-09-08 Taisho Pharmaceut Co Ltd ゲル状徐放性組成物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 011, no. 353 (C - 457) 18 November 1987 (1987-11-18) *
PATENT ABSTRACTS OF JAPAN vol. 013, no. 079 (C - 571) 22 February 1989 (1989-02-22) *
PATENT ABSTRACTS OF JAPAN vol. 098, no. 014 31 December 1998 (1998-12-31) *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1646367A2 (fr) * 2003-07-21 2006-04-19 Bio-Dar Ltd. Formes dosifiees a liberation controlee a base de gomme gellane a administrer par voie orale, une nouvelle technologie pour la retention gastrique
EP1646367A4 (fr) * 2003-07-21 2011-06-15 Nesher Solutions Ltd Formes dosifiees a liberation controlee a base de gomme gellane a administrer par voie orale, une nouvelle technologie pour la retention gastrique
US9789191B2 (en) 2010-09-13 2017-10-17 Solixa Technologies, Inc. Aqueous drug delivery system
US9132291B2 (en) 2010-10-05 2015-09-15 Dfb Technology, Ltd. Water-in-oil emulsion compositions containing gellan gum for topical delivery of active ingredients to the skin or mucosa
ITUB20156821A1 (it) * 2015-12-09 2017-06-09 Altergon Sa CAPSULE DI GELATINA MOLLE A RILASCIO pH INDIPENDENTE
WO2017097612A1 (fr) * 2015-12-09 2017-06-15 Altergon S.A. Capsules de gélatine molle à libération indépendante du ph
RU2738933C2 (ru) * 2015-12-09 2020-12-18 Альтергон С.А. Мягкие желатиновые капсулы с рН-независимым высвобождением
US11304910B2 (en) 2015-12-09 2022-04-19 Altergon S.A. Soft gelatin capsules with pH-independent release

Also Published As

Publication number Publication date
EP1027072A1 (fr) 2000-08-16
JP2004500305A (ja) 2004-01-08
AU1292199A (en) 1999-05-24
AU744328B2 (en) 2002-02-21
CA2308291A1 (fr) 1999-05-14

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