WO1985005029A1 - Insuline administree par voie orale et son procede de preparation - Google Patents

Insuline administree par voie orale et son procede de preparation Download PDF

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Publication number
WO1985005029A1
WO1985005029A1 PCT/US1985/000859 US8500859W WO8505029A1 WO 1985005029 A1 WO1985005029 A1 WO 1985005029A1 US 8500859 W US8500859 W US 8500859W WO 8505029 A1 WO8505029 A1 WO 8505029A1
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WO
WIPO (PCT)
Prior art keywords
insulin
phase
composition
coacervate
particles
Prior art date
Application number
PCT/US1985/000859
Other languages
English (en)
Inventor
Bernard Ecanow
Charles S. Ecanow
Original Assignee
Medaphore Inc.
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 Medaphore Inc. filed Critical Medaphore Inc.
Publication of WO1985005029A1 publication Critical patent/WO1985005029A1/fr

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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
    • A61K9/48—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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes

Definitions

  • This invention concerns an improved form of insulin which is orally administered, and methods of preparation.
  • liposomes to prepare an oral form of insulin is based upon a concept and a method manu ⁇ facture that differs fundamentally from the concept and method of the herein disclosed invention.
  • a two phase coacervate system comprises the basis of this invention; it bears no relationship to liposomes.
  • compositions do not appear to be the basis on which, a useful oral insulin may be developed.
  • an oral dosage form of insulin will elim ⁇ inate or reduce the need to use injection as the mode of administering insulin. Further, it appears that an oral form of insulin could be used to advantage in the treat ⁇ ment of adult onset diabetes mellitus.
  • the sulfonylureas are now prescribed for the treatment of this form of diabetes despite the adverse effects associated with the use of this class of drugs. The sulfonylureas are not considered to be an acceptable substitute for insulin nor are they considered to be oral forms of insulin.
  • the present invention discloses an oral dosage form of insulin and a method by which said insulin can be prepared.
  • the herein disclosed invention constitutes a safe, effective oral dosage form not only for insulin but for non-polar drugs and other medical compositions known to be subject to degradation in the digestive system.
  • insulin When insulin is incorporated in the herein disclosed delivery system it retains all of its known pharmacologic and physiological properties. Furthermore, this invention provides a convenient method of preparation of the claimed oral dosage forms.
  • the invention provides a composition of matter useful as an oral dosage form of insulin; said preparation comprising a non-toxic two phase liquid system, both phases being aqueous; a) one of said phases being a relatively non- polar coacervate phase; b) The other of said phases being a relatively polar liquid aqueous phase; c) said relatively non-polar coacervate phase being insoluble in and in equilibrium with said relatively polar liquid aqueous phase; d) said two phase system, when prepared to contain an insulin component or components in the co ⁇ acervate phase of the coacervate system, yields a delivery system for the oral administration of insulin.
  • the invention provides for a method of preparing a composition useful as an oral dosage form of insulin, said method based upon the two phase liquid system.
  • a preferred method is characterized by the steps of (a) combining albumin and lecithin in equal propor ⁇ tions in sterile water; (b) thoroughly mixing the com ⁇ ponents; (c) storing said mixture undisturbed until the composition of step (a) separates into two layers, one above the other, the lower phase being a substantially non-polar coacervate " phase, the upper phase being an equilibrium water phase; (d) continuing the separation process until no increase in the volume of the coacervate system can be observed; (e) centrifuging the composition until inspection reveals a clear demarcation of the two phases and (f) separating the two phases.
  • the herein disclosed invention represents a significant scientific and medical advance.
  • any one of a number of appropriate non-toxic coacervate systems as a beginning step in the manufacture of this invention, it becomes possible, through a subsequent sequence of relatively simple processing steps to produce a delivery system for the oral administration of insulin.
  • the said system can be produced as a liquid or as an encapsulated composition-
  • the term particle refers to encapsulated or emulsion droplet entities.
  • the size of the particles which will contain the hemoglobin component may range from nanometer size to micron -size; from 10 ⁇ 8 microns to 10 microns. Particles in this range of sizes are known to pass through the wall of the small intestine and, it follows, into the cir ⁇ culatory system. There is reason to believe that in the finished product of this invention, the coacervated micro and sub-micro encapsulated particles will tend to adhere to the membrane of the gastrointestinal tract, thereby facilitating passage through the wall of the small in ⁇ testine.
  • Another singularly important feature of this invention is the protection afforded the insulin component Q£ this composition from enzymatic degradation in the digestive tract. This is accomplished by incorporating the insulin in the coacervate phase of the coacervate system. In the process of this incorporation, a film of coacervate phase water surrounds and coats each insulin molecule. This feature is of fundamental importance since coacervate phase water differs in physical chemical structure from the bulk water present in the stomach. The digestiveenzymes whichdegrade insulin readily diffuse in the aforementioned bulk water, however, since these en ⁇ zymes diffuse only minimally, if at all, in the water of the coacervate phase. The rate of interaction between the insulin component and the digestive enzyme is extremely slow.
  • the rate of interaction is so slow, physio ⁇ logically useful quantities of insulin escape destruction, pass through the wall of the small intestine and into the circulation.
  • the insulin component is protected from the degradation effects of pH, acid-base balance and other conditions and processes of the gastrointestinal tract.
  • any of the known forms of insulin i.e., regular insulin, globin zinc insulin, insulin zinc suspension, prompt insulin zinc suspension, extended insulin zinc suspension, or combinations thereof may be used.
  • the insulins used in this invention may be of U.S.P. standard, if desired. Non U.S.P. insulins may be used provided they are accept ⁇ able in other fundamental respects.
  • the insulin component may be comprised of recrystallized insulin obtained from animal, recombinant genetic, synthetic or other sources. Since the claimed compositions are intended only for oral use, the insulin used in this invention need not be subjected to the rigorous manufacturing steps required for U.S.P. injectable insulin. However, if desired, insulin pre ⁇ pared for injection may be used in this invention.
  • the claimed composition may be prepared to any of several specifications. Thus, it may consist of insulin dispersed in the disclosed coacervate system and dispensed as a liquid preparation.
  • the method of this invention also provides for additional steps in which the previously described preparation is further processed to yield a product which is comprised of particles of encapsulated insulin. The particles are within the size range referred to previously.
  • the final product can be placed in conventional gelatin capsules and dispensed as such, or alternatively, the particles containing insulin can be dispensed in any suitable liquid vehicle, i.e., a vehicle based on coacervate phase water and dispensed for use in that form.
  • the invention provides for sus ⁇ tained release dosage forms and for emulsion and suspen ⁇ sion preparations.
  • any appropriate non-toxic coacervate system can be used in the manufacture of the product of this invention.
  • any endogenous biological surface active agent or derivatives thereof e.g., albumin, lecithin, gelatin, etc.
  • suitable non-toxic exogenous components can also be used to prepare the coacervate system, for example, acacia when combined with gelatin.
  • surface active agents and/or combinations thereof that can form multiple coacervate phase systems can also be used.
  • the first manufacturing step involves this preparation of an appropriate coacervate system.
  • the coacervate system Upon completion of this step, the coacervate system will consist of two phases: (1) an internal suspension, re ⁇ latively non-polar phase, commonly referred to as the coacervate phase, and (2) an associated, relatively polar, external suspension or equilibrium phase. These phases are insoluble in and in equilibrium with each other.
  • the coacervate phase of the disclosed coacervate system can comprise from 0.5 to 99.5% by volume of the system; correspondingly, the associated equilibrium phase can _, comprise from 0.5 to 99.5% by volume of the herein described coacervate system.
  • preparation of an appropriate coacervate system comprises the first step in the manufacuture of the claimed composition of matter.
  • the said coacervate system may be formulated using any acceptable non-toxic biological, non-biological surface active agent, derivatives or mixtures thereof.
  • Sources of the surface active agent component may be either of natural or synthetic origin. Any of the following are examples of acceptable surface active agents: albumin, suitable phospholipids, gelatin . , modified fluid gelatin, acacia gel and other surface active compositions known to those skilled in the art. In this invention, appro ⁇ priate combinations of these agents are preferred.
  • the combination- of albumin and a phospholipid preferably lecithin is preferred.
  • phospholipids such as cephalin, iso- lecithin, sphingomyelin, phosphatidyl serine, phosphatidic acid, phosphatidyl inositol and phosphatidyl choline may be used in place of the preferred lecithin.
  • equal weight to volume proportions of albumin and lecithin are added to a quantity of sterile water that will yield 100 mis of aqueous solution. Any quantity of albumin and lecithin can be used, provided that the proportions given above are observed and the quantity of water is adjusted accordingly. Three per cent weight to volume of lecithin and three per cent weight tc volume of albumin is preferred. Unequal proportions of these compositions may be used to produce a coacervate system; however, while such systems may have useful character ⁇ istics, unequal proportions are not believed to be pre ⁇ ferable i.e.; drug transport, etc., for this invention. In the method of this invention, other com ⁇ binations of surface active agents may be used.
  • acacia gel and gelatin or modified gelatin two gelatins of the same or differing isoelectric points, two modified fluid gelatins of the same or differing isoelectric points and other combinations of surface active agents known to those skilled in the art.
  • the solution is thoroughly mixed and stored, undisturbed in suitable containers.
  • the storage step takes place at a temper ⁇ ature which can range from the freezing point to 4° C to room temperature. In the disclosed preferred method storage takes place at any temperature within the range of 4° to 15° C.
  • the solution described above will separate into two phases.
  • the upper phase (layer) is referred to as the equilibrium water phase.
  • the lower phase (layer) is referred to as the coacervate phase.
  • the period of storage is continueduntil the maximum yield of the coacervate phase of the coacervate system has been achieved. Maximum yield is the point in the manufacturing process at which no significant increase in the volume of the coacervate phase can be observed. This determination may be made by visual inspection or other suitable means. As is known to those skilled in theart, longer periods of storage will produce greater yields of the coacervate phase.
  • the coacervate system is centrifuged until observation indicates that a clear division exists at the interface of the two phases of the coacervate system. At this point, the two phases are separated from each other by means of a separatory funnel. The desired amount and type of insulin is then added to the coacervate phase and mixed thoroughly.
  • any of the known forms and dosages of insulin i.e., regular insulin, globin zinc insulin, insulin zinc suspension, prompt insulin zinc suspension, extended insulin zinc suspension, protamine zinc insulin or com ⁇ bination thereof may be used.
  • the insulin(s) used may be of U.S. . standard. If preferred, the insulin component may be one directly derived from recrystallization of insulin from animal, recombinant genetic or other sources.
  • the invention contemplates the manufacutre of a variety of oral insulin preparations, compositions and dosages in order to meet specific medical requirements. Accordingly, no single insulin specification can be described as pre ⁇ ferred.
  • the individual dose can be 100 standard units and/or fractions and/or multiples thereof.
  • the preparation may be dispensed as an oral dosage form of insulin.
  • the manufacturing process is continued. In that case, the next procedure involves the recombination of the equilibrium water phase and the coacervate phase which now contains the insulin component.
  • the preparation is emulsified using a colloid mill, sonifier or other emulsifying technique known to those skilled in the art.
  • the particles of the emulsion may range in size from 10 —8 microns to 10 microns. It is preferred that the particle size be within the nanometer and millimicron range.
  • the product resulting from the emulsifying step comprises a prompt release form of insulin and may be used as such or stored under refrigeration until needed.
  • the emulsified composition is, if desired, processed further to produce time release, i.e., sustained release forms of insulin(s).
  • time release i.e., sustained release forms of insulin(s).
  • the preparation is subjected to a heating step, i.e., the preparation is heated for from 30 seconds to 15 minutes at a temperature which may range from 20° to 70° C. Since this step will harden the surface film surrounding each particle, the variables of time and temperature may be varied to produce a spectrum of particle surface film hardnesses.
  • This method comprises the preferred method.
  • Other processes may be used to prepare sustained release forms of the claimed compo ⁇ sition.
  • a cross linking agent such as a non-toxic entity within the aldehyde group, i.e., gluteraldehyde may be used in a chemical process which harden the film surface of the particles
  • the claimed oral insulin composition is comprised of particles which are characterized by differing degrees of surface film hard ⁇ ness and thus, differing rates of time release.
  • the composition is filtered through a filter pad.
  • the product remaining in the filter bed constitutes the particles of oral insulin. These are removed from the filter bed by a washing step and then dried by any acceptable drying process.
  • the preparation of particles containing oral insulin is completed.
  • the composition may now be placed in an appropriate oral dosage form.
  • the desired dose of the composition may be re- suspended in a suitable non-toxic liquid vehicle, or placed in other conventional oral dosage forms and dis ⁇ claimedd or stored, preferably under refrigeration until needed.
  • an appropriate dose of the prompt release particles may be mixed with an appropriate dose of the previously described time release oral insulin(s) formulation. This mixture is then placed in any acceptable, non-toxic oral dosage form and dispensed or stored, preferably under refrigeration until needed.
  • the two phases are separated by means of a separatory funnel.
  • the desired quantity and type of insulin or combinations thereof, as described above, are then added and mixed into the coacervate phase, and may, if desired, be dispensed as oral liquid insulin. If pre ⁇ ferred, the manufacturing process proceeds and the two previously separated phases, one of which now contains insulin, are recombined.
  • an emulsion consisting of nanometer, millimicron and micron size particles inside of which insulin is contained is prepared. The emulsion is simultaneously rapidly cooled * and stirred at a temperature of from 0 to 10°C for from 15 to 60 minutes by means of a refrigerated stirring unit.
  • the composition is forced through a filtering system.
  • the product remaining in the filter bed is removed through a washing step.
  • the particles are dried in an air drying system.
  • the quantity and type of insulin necessary for a specific dose is placed in any appropriate oral drug delivery system.
  • the conventional gelatin capsule is preferred.
  • Example 1_ 5% weight to volume proportions of albumin and lecithin are added to an amount of distilled water that will yield 100 mis of aqueous solution. The mixture is then thoroughly mixed by a vortex mixer. Following the mixing step, the solution is stored undisturbed until the max ⁇ imum yield of the coacervate phase of the coacervate system has been achieved. The storage step takes place at 4°C. When it is observed that the maximum yield of the coacervate phase has been achieved, the coacervate..system is centrifuged until observation indicates that a clear division exists at the interface of the two phases of the coacervate system. The two phases are then separated by means of a separatory funnel.
  • the equilibrium water phase resulting from this separation step is set aside for sub ⁇ sequent recombination with the coacervate phase.
  • 100 standard units of regular insulin U.S. . is thoroughly mixed into the coacervate phase.
  • the two phases are recombined and subjected to an emulsifying procedure to produce an emulsion, the particles of which will range from the nanometer to the millimicron size.
  • the emulsified product comprises a prompt release form of insulin and may be used as such or stored, preferably under refrigeration,until needed.
  • Example 2 The method-of Example 1 is followed except that Extended Insulin Zinc Suspension U.S.P. is used in place of regular insulin and the particles removed from the filtration bed are placed in gelatin capsules in doses that are medically appropriate.
  • Example 3_ The method of Example 1 is followed except that Prompt Insulin Zinc Suspension U.S.P. is used in place of regular insulin.
  • Example 4_ The method of Example 1 is used except that G lo b in Zinc Insulin Suspension U.S,P. is; used in place of regular insulin.
  • a mixture of the produce of the emulsification step and the product subjected to the heat ⁇ ing step is prepared and dispensed in an appropriate liquid dosage form.
  • Example 5_ The method of Example 1 is used except that Protamine Zinc Insulin is used in place of regular insulin.
  • Example 6_ The method of Example 1 is used except that a mixture of regular insulin U.S.P. and Insulin Zinc Sus ⁇ pension U.S.P. are used in place of regular insulin.
  • Example 7_ 200 mis of 5% solution of albumin is added to 200 is of 3% solution of lecithin and mixed thoroughly. The remaining steps of the procedure follow those of Example 1, except that Protamine Zinc Insulin are used in place of regular insulin.
  • Example 8_ 200 is of a 5% solution of albumin is added to 200 mis of a 7% solution of lecithin and mixed thoroughly. The remaining steps of the procedure follow Example 1, except that Globulin Zinc Insulin Suspension U.S.P. is used in place of Regular Zinc Insulin.
  • Example 9_ 200 mis of a 3% solution of albumin is thoroughly mixed with 200 mis of a 3% solution of isolecithin. The solution is then stored undisturbed at 4°C for 24 hours. The remaining steps of the procedure follow Example 1.
  • Example 10 Disperse 6% gelatin solution in distilled water and heat to 40°C. Next, slowly add that amount of sodium chloride to the solution as will result in a two phase system.
  • The. lower layer comprises the colloid rich liquid gelatin phase
  • the upper layer constitutes the coacervate phase.
  • the two phases are separated and 100 units of regular insulin U.S.P. is added to the coacervate phase.
  • Recombine the two phases mix thoroughly and through the use of a colloid mill prepare an emulsion of the recombined phases wherein the size of the particles of said emulsion are in the range of 10 microns •
  • the emulsion is simultaneously rapidly cooled and stirred at a temperature of 5°C for 30 minutes.
  • the resulting particles are thoroughly rinsed with distilled water following which they are completely dried.
  • the quantity of the composition placed in gelatin capsules is a function of the medically indicated dosage of insulin or combinations thereof.
  • the particles are then placed in gelatin capsules in the dosages and types of insulin desired.
  • Example 11 The method of Example 9 is followed except that Isophane Insulin Suspension U.S.P. is used in place of regular insulin U.S.P.
  • Example 12 The method of Example 1 is followed except that ExtendedInsulin Zinc Suspension U.S.P. is used in place of Regular Insulin U.S.P.
  • Example 13 The method of Example 1 is followed except that Lente Insulin is used in place of regular insulin.
  • Example 14 The method of Example 1 is followed except that recrystallized insulin directly derived from animal sources is used in place of Regular Insulin U.S.P.
  • Example 15 The method of Example 1 is used except that a combination of regular and globin zinc insulin are used in place of regular insulin.
  • Example 16 200 mis of a 3% solution of albumin is thoroughly mixed with 200 mis of a 3% solution of iso- lecithin. The solution is then stored undisturbed at 4°C for 24 hours. The remaining steps of the. procedure follow Example 1, except that Prompt Insulin Zinc Suspension U.S.P. is used in place of regular insulin U.S.P.
  • Example 17 The method of Example 1 is used except that a combination of Regular Insulin U.S.P., Prompt Zinc Suspension and Extended Insulin Zinc Suspension is used in place of regular insulin.
  • Example 18 The method of Example 1 is used except that after the two phases of the coacervate system are separated, 10 units of regular insulin are dispersed into the coacervate phase and mixed thoroughly. The composi ⁇ tion is then dispensed as oral liquid insulin or placed in refrigerated storage until it is to be dispensed.
  • Example 19 The method of Example 10 is followed except that after two phases of the system are separated 20 units of insulin are dispersed in the coacervate phase and mixed thoroughly. The preparation can either be dispensed as an oral liquid insulin preparation or stored until needed.
  • Example 20 Example 1 is followed except that the final product of said example is heated for 20 seconds at a temperature of 40°C. Following the heating step, the composition is forced through a filter bed. The product remaining in the filter bed is removed through a washing procedure andthen dried. Upon completing of the drying step, the composition may be placed in any acceptable oral dosage vehicle in the indicated dose.
  • Example 21 Example 1 is followed except that the heating step is carried out for 10 seconds at 35° C.
  • Example 22 Example 1 is followed except that 0.5% weight to volume of gluteraldehyde is added to the final product of said example.
  • the composition is mixed thoroughly and then subjected to a filtering step.
  • the particulate matter remaining in the filter bed is removed and placed in refrigerated storage for three to five hours, after which the composition is washed with distilled water until no trace of the gluteraldehyde is found in the wash water.
  • This step is followed by a period of drying, after which the product of the drying step may be placed in any suitable dose in any conventional oral dosage vehicle.

Abstract

Une composition est utile en tant que forme d'insuline de dosage par voie orale basée sur un système liquide aqueux à deux phases dans lequel le ou les composants d'insuline sont incorporés. L'invention décrit également un procédé de préparation de la forme d'insuline de dosage par voie orale ainsi qu'un autre procédé permettant de produire des formes d'insuline administrées par voie orale de dosage à libération entretenue. La forme d'insuline par voie orale élimine ou réduit le besoin d'utiliser l'injection pour administrer l'insuline.
PCT/US1985/000859 1984-05-09 1985-05-08 Insuline administree par voie orale et son procede de preparation WO1985005029A1 (fr)

Applications Claiming Priority (2)

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US60848384A 1984-05-09 1984-05-09
US608,483 1984-05-09

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WO1985005029A1 true WO1985005029A1 (fr) 1985-11-21

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US5179079A (en) * 1986-12-16 1993-01-12 Novo Nordisk A/S Nasal formulation and intranasal administration therewith
DE4140192A1 (de) * 1991-12-05 1993-06-09 Alfatec-Pharma Gmbh, 6900 Heidelberg, De Sol-gesteuerte thermokolloidmatrix auf gelatinebasis fuer perorale retardformen
WO1993010767A1 (fr) * 1991-12-05 1993-06-10 Alfatec-Pharma Gmbh Forme d'administration perorale de medicaments peptidiques, notamment l'insuline
DE4140195A1 (de) * 1991-12-05 1993-06-17 Alfatec Pharma Gmbh Pharmazeutisch applizierbares nanosol und verfahren zu seiner herstellung
WO1993013753A1 (fr) * 1992-01-17 1993-07-22 Alfatec-Pharma Gmbh Comprimes contenant des medicaments peptidiques, leur fabrication et leur application
EP0552256A1 (fr) * 1990-10-10 1993-07-28 Autoimmune, Inc. Methodes servant a traiter ou a prevenir le diabete du type 1 par administration orale d'insuline
AU671965B2 (en) * 1991-12-05 1996-09-19 Alfatec-Pharma Gmbh Pharmaceutically Applicable Nanosol and Process for Preparing The Same
US5614219A (en) * 1991-12-05 1997-03-25 Alfatec-Pharma Gmbh Oral administration form for peptide pharmaceutical substances, in particular insulin
WO1998035656A1 (fr) * 1997-02-12 1998-08-20 R. P. Scherer Corporation Procede de preparation de formes galeniques solides
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WO2009055331A2 (fr) 2007-10-22 2009-04-30 Schering Corporation Dérivés hétérocycliques bicycliques et leurs procédés d'utilisation
WO2009143049A1 (fr) 2008-05-19 2009-11-26 Schering Corporation Dérivés hétérocycliques bicycliques et leur utilisation en tant que modulateurs de gpr119
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WO2010075269A1 (fr) 2008-12-23 2010-07-01 Schering Corporation Dérivés de pyrimidine en tant que modulateurs de rcpg pour une utilisation d'un traitement de l'obésité et du diabète
WO2010075068A1 (fr) 2008-12-16 2010-07-01 Schering Corporation Dérivés de pyridopyrimidine et leurs procédés d'utilisation
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