MICROPARTICLES CONTAINING PEG AND/OR PEG GLYCERYL ESTERS

Abstract: Microparticles containing bioaffecting agents can be made via thermoforming techniques in the presence of one or more processing aids. The microparticles have generally consistent shape, size and release/taste properties.

Description: MICROPARTICLES CONTAINING PEG AND/OR PEG GLYCERYL ESTERS Field of the Invention The invention deals with microparticles that are produced from compositions containing bio-affecting agents at least one processing aid. The microparticles generally have very consistent properties and can be readily coated or otherwise processed to yield dosage forms, or comestible units, having taste-masking and/or controlled release features. The microparticles are useful in making comestible units for delivery of the bio-affecting agents via oral, transdermal, or other routes of administration. Background The nutritional/therapeutic use of microparticles containing bio-affecting agents, i.e., drugs, is known. However, the production of microparticles~and especially microspheres—having highly consistent shape, size and other properties can be problematic. That is, conventional microparticles may suffer from inconsistencies of shape, size, etc. which can lead to problems during coating, formulating and/or shaping operations used to produce comestible units. Applicants' assignee, Fuisz Technologies, owns several patents which deal with the use of thermoforming techniques to facilitate the production of microparticulates useful in delivery systems for bio-affecting agents. Among these patents are: U.S. 5,567,439 deals with controlled release dosage forms containing shearform matrix (floss) particles which were ground and employed, along with a glycerol polyethylene glycol behenate in making tablets. See Example 1 therein. U.S. 5,683,720 refers to discrete microspheres made under liquiflash conditions. The microspheres can be coated and are useful in pharmaceutical products. In addition, the use of polyethylene glycols (PEG's) in the production of dosage units is known. U.S. 4,744,976 is concerned with sustained release dosage forms containing a bioaffecting agent in an erodible matrix. The matrix contains a PEG having a molecular weight between 1,000 and 20,000. U.S. 5,290,569 is directed to the use of PEG's of 400 to 20,000 molecular weight as granulating/binding agents for active agents. The agents are melt granulated with the PEG, then coated with a generally lower melting material. U.S. 5,403,593 shows melt granulated compositions which employ PEG's as granulating media. Sustained release products are made therewith. U.S. 5,429,825 deals with a rotomelt granulation process that employs PEG 4000 or PEG 6000 as a binder. See column 5, lines 67-8. Nonetheless, a need exists for compositions and processes that produce microparticles, especially microspheres, having highly uniform, or consistent, properties. This invention addresses that need. Summary of the Invention The invention deals with uniform microparticles comprising (a) at least one bioaffecting agent and (b) at least one processing aid selected from (i) high molecular weight polyethylene glycols and (ii) polyethylene glycol glyceryl esters. Owing to the presence of one or both of the processing aids described herein, the microparticles containing them have consistent shape and size. That consistency make them readily processable into comestible units or dosage forms via conventional processing techniques. When controlled release agent(s) or taste-masking systems are used in or on the microparticles, these properties are also generally consistent throughout the controlled release and/or taste- masked products produced. In preferred embodiments, the microparticles are microspheres and the processing aids are used in binary combinations in which each functions as a spheronization aid. Applicants have discovered that certain processing aids, namely one or both of certain PEG's and certain glyceryl esters of same are useful in making microparticles having highly consistent properties. Detailed Description of the Invention The invention is concerned with bio-affecting microparticles produced from compositions containing a unique combination of ingredients. The composition, the microparticles, their production and comestible units containing them are disclosed. Unless stated otherwise, all percentages recited herein are weight percentages, based on total composition weight. I. Compositions The compositions of the invention employ optional excipients with (a) a bioaffecting agent and (b) one or more processing aids. A. Bio-affecting Agents The active ingredients useful herein can be selected from a large group of therapeutic agents. Respective classes include those in the following therapeutic categories: ace-inhibitors; alkaloids; antacids; analgesics; anabolic agents; anti-anginal drugs; anti-allergy agents; anti-arrhythmia agents; antiasthmatics; antibiotics; anticholesterolemics; anticonvulsants; anticoagulants; antidepressants; antidiarrheal preparations; anti-emetics; antihistamines; antihypertensives; anti-infectives; anti- inflammatories; antilipid agents; antimanics; anti-migraine agents; antinauseants; antipsychotics; antistroke agents; antithyroid preparations; anabolic drugs; antiobesity agents; antiparasitics; antipsychotics; antipyretics; antispasmodics; antithrombotics; antitumor agents; antitussives; antiulcer agents; anti-uricemic agents; anxiolytic agents; appetite stimulants; appetite suppressants; beta-blocking agents; bronchodilators; cardiovascular agents; cerebral dilators; chelating agents; cholecystekinin antagonists; chemotherapeutic agents; cognition activators; contraceptives; coronary dilators; cough suppressants; decongestants; deodorants; dermatological agents; diabetes agents; diuretics; emollients; enzymes; erythropoietic drugs; expectorants; fertility agents; fungicides; gastrointestinal agents; growth regulators; hormone replacement agents; hyperglycemic agents; hypoglycemic agents; ion-exchange resins; laxatives; migraine treatments; mineral supplements; mucolytics, narcotics; neuroleptics; neuromuscular drugs; non-steroidal anti- inflammatories (NSAIDs); nutritional additives; peripheral vasodilators; polypeptides; prostaglandins; psychotropics; renin inhibitors; respiratory stimulants; sedatives; steroids; stimulants; sympatholytics; thyroid preparations; tranquilizers; uterine relaxants; vaginal preparations; vasoconstrictors; vasodilators; vertigo agents; vitamins; wound healing agents; and others. Active agents which may be used in the invention include: acetaminophen; acetic acid; acetylsalicylic acid, including its buffered forms; acrivastine; albuterol and its sulfate; alcohol; alkaline phosphatase; allantoin; aloe; aluminum acetate, carbonate, chlorohydrate and hydroxide; alprozolam; amino acids; aminobenzoic acid; amoxicillin; ampicillin; amsacrine; amsalog; anethole; ascorbic acid; aspartame; astemizole; atenolol; azatidine and its maleate; bacitracin; balsam peru; BCNU (carmustine); beclomethasone diproprionate; benzocaine; benzoic acid; benzophenones; benzoyl peroxide; benzquinamide and its hydrochloride; bethanechol; biotin; bisacodyl; bismuth subsalicylate; bornyl acetate; bromopheniramine and its maleate; buspirone; caffeine; calamine; calcium carbonate, casinate and hydroxide; camphor; captopril; cascara sagrada; castor oil; cefaclor; cefadroxil; cephalexin; centrizine and its hydrochloride; cetyl alcohol; cetylpyridinium chloride; chelated minerals; chloramphenicol; chlorcyclizine hydrochloride; chlorhexidine gluconate; chloroxylenol; chloropentostatin; chlorpheniramine and its maleates and tannates; chlorpromazine; cholestyramine resin; choline bitartrate; chondrogenic stimulating protein; cimetidine and its hydrochloride; cinnamedrine hydrochloride; citalopram; citric acid; clarithromycin; clemastine and its fumarate; clonidine and its hydrochloride salt; clorfibrate; cocoa butter; cod liver oil; codeine and its fumarate and phosphate; cortisone acetate; ciprofloxacin HC1; cyanocobalamin; cyclizine hydrochloride; cyproheptadine and its hyddrochloride; danthron; dexbromopheniramine maleate; dextromethorphan and its hydrohalides; diazepam; dibucaine; dichloralphenazone; diclofen and its alkali metal sales; diclofenac sodium; digoxin; dihydroergotamine and its hydrogenates/mesylates; diltiazem; dimethicone; dioxybenzone; diphenhydramine and its citrate; diphenhydramine and its hydrochloride; divalproex and its alkali metal salts; docusate calcium, potassium, and sodium; doxycycline hydrate; doxylamine succinate; dronabinol; efaroxan; enalapril; enoxacin; ergotamine and its tartrate; erythromycin; estropipate; ethinyl estradiol; ephedrine; epinephrine bitartrate; erythropoietin; eucalyptol; famotidine; fenoprofen and its metal salts; ferrous fumarate, gluconate and sulfate; fluoxetine; folic acid; fosphenytoin; 5- fluorouracil (5-FU); fluoxetine and its hydrochloride; flurbiprofen; furosemide; gabapentan; gentamicin; gemfibrozil; glipizide; glycerine; glyceryl stearate; granisetron and its hydrochloride; griseofulvin; growth hormone; guafenesin; hexylresorcinol; hydrochlorothiazide; hydrocodone and its tartrates; hydrocortisone and its acetate; 8- hydroxyquinoline sulfate; hydroxyzine and its pamoate and hydrochloride salts; ibuprofen; indomethacin; inositol; insulin; iodine; ipecac; iron; isosorbide and its mono- and dinitrates; isoxicam; ketamine; kaolin; ketoprofen; lactic acid; lanolin; lecithin; leuprolide acetate; lidocaine and its hydrochloride salt; lifinopril; liotrix; loratadine; lovastatin; luteinizing hormore; LHRH (lutenizing hormone replacement hormone); magnesium carbonate, hydroxide, salicylate, and trisilicate; meclizine and its hyddrochloride; mefenamic acid; meclofenamic acid; meclofenamate sodium; medroxyprogesterone acetate; methenamine mandelate; menthol; meperidine hydrochloride; metaproterenol sulfate; methscopolamine and its nitrates; methsergide and its maleate; methyl nicotinate; methyl salicylate; methyl cellulose; methsuximide; metoclopramide and its halides/hydrates; metronidazole and its hydrochloride; metoprotol tartrate; miconazole nitrate; mineral oil; minoxidil; morphine; naproxen and its alkali metal sodium salts; nifedipine; neomycin sulfate; niacin; niacinamide; nicotine; nicotinamide; nimesulide; nitroglycerine; nonoxynol-9; norethindrone and its acetate; nystatin; octoxynol; octoxynol- 9; octyl dimethyl PABA; octyl methoxycinnamate; omega-3 polyunsaturated fatty acids; omeprazole; ondansetron and its hydrochloride; oxolinic acid; oxybenzone; oxtriphylline; para-aminobenzoic acid (PABA); padimate-O; paramethadione; pentastatin; peppermint oil; pentaerythritol tetranitrate; pentobarbital sodium; perphenazine; phenelzine sulfate; phenindamine and its tartrate; pheniramine maleate; phenobarbital; phenol; phenolphthalein; phenylephrine and its tannates and hydrochlorides; phenylpropanolamine and its hydrochloride salt; phenytoin; pirmenol; piroxicam and its salts; polymicin B sulfate; potassium chloride and nitrate; prazepam; procainamide hydrochloride; procaterol; promethazine and its hydrochloride; propoxyphene and its hydrochloride and napsylate; pramiracetin; pramoxine and its hydrochloride salt; prochlorperazine and its maleate; propanolol and its hydrochloride; promethazine and its hydrochloride; propanolol; pseudoephedrine and its sulfates and hydrochorides; pyridoxine; pyrolamine and its hydrochlorides and tannates; quinapril; quinidine gluconate and sulfate; quinestrol; ralitoline; ranitadine; resorcinol; riboflavin; salicylic acid; scopolamine; sesame oil; shark liver oil; simethicone; sodium bicarbonate, citrate, and fluoride; sodium monofluorophosphate; sucralfate; sulfanethoxazole; sulfasalazine; sulfur; sumatriptan and its succinate; tacrine and its hydrochloride; theophylline; terfenadine; thiethylperazine and its maleate; timolol and its maleate; thioperidone; tramadol; trimetrexate; triazolam; tretinoin; tetracycline hydrochloride; tolmetin; tolnaf ate; triclosan; trimethobenzamide and its hydrochloride; tripelennamine and its hydrochloride; tripolidine hydrochloride; undecylenic acid; vancomycin; verapamil HC1; vidaribine phosphate; vitamins A, B, C, D, Bi, B 2 , B 6 , B 12 , E, and K; witch hazel; xylometazoline hydrochloride; zinc; zinc sulfate; zinc undecylenate. Mixtures and pharmaceutically acceptable salts of these and other actives can be used. Particularly useful active agents are sparingly soluble solid agents whose dissolution and release properties are enhanced by the solubilizing agents used herein. These agents include H 2 antagonists, analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs), anticholesterolemics, anti-allergy agents, and anti-migraine agents. Analgesics include aspirin, acetaminophen, acetaminophen plus caffeine, and non- steroidal anti-inflammatory drugs (NSAIDS), e.g., ibuprofen and nimesulide. Useful NSAIDs include ibuprofen; diclofenac and its alkali metal salts; fenoprofen and its metal salts; fluriprofen; ketoprofen; naproxen and its alkali metal salts; nimesulide; and piroxicam and its salts. H 2 -antagonists which are contemplated for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine. Useful anti-allergy agents include hydricodone and its tartrates; clemastine and its fumarate; azatadine and its maleate; acetaminophen; hydroxyzine and its pamoate and hydrochloride salts; chlorpheniramine and its maleates and tannates; pseudoephedrine and its sulfates and hydrochlorides; bromopheniramine and its maleate; dextromethorphan and its hydrohalides; loratadine; phenylephrine and its tannates and hydrochlorides; methscopolamine and its nitrates; phenylpropanolamine and its hydrochlorides; codeine and its hydrochloride; codeine and its phosphate; terfenadine; acrivastine; astemizole; cetrizine and its hydrochloride; phenindamine and its tartrate; tripelennamine and its hydrochloride; cyproheptadine and its hydrochloride; promethazine and its hydrochloride; and pyrilamine and its hydrochlorides and tannates. Useful antimigraine agents include divalproex and its alkali metal salts; timolol and its maleate; propanolol and its hydrohalides; ergotamine and its tartrate; caffeine; sumatriptan and its succinate; dihydroergotamme, its hydrogenates/mesylates; methsergide and its maleate; isometheptene mucate; and dichloralphenazone. Another class of drugs which can be used are antiemetics. Useful antiemetics include: meclizine and its hydrochloride; hydroxyzine and its hydrochloride and pamoate; diphenhydramine and its hydrochloride; prochlorperazine and its maleate; benzquinamide and its hydrochloride; granisetron and its hydrochloride; dronabinol; bismuth subsalicylate; promethazine and its hydrochloride; metoclopramide and its halides/hydrates; chlorpromazine; trimethobenzamide and its hydrochloride; thiethylperazine and its maleate; scopolamine; perphenazine; and ondansetron and its hydrochloride. Other active ingredients for use in the present invention include antidiarrheals such as immodium AD, antihistamines, antitussives, decongestants, vitamins, and breath freshners. Also contemplated for use herein are anxiolytics such as Xanax; antipsychotics such as Clozaril and Haldon; antihistamines such as Seldane, Hismanal, Relafen, and Tavist; antiemetics such as Kytril and Cesamet; bronchodilators such as Bentolin, Proventil; antidepressants such as Prozac, Zoloft, and Paxil; antimigranes such as Imigran, ACE-inhibitors such as Nasotec, Capoten and Zestril; Anti-Alzheimers agents such as Νicergoline; and Ca π -Antagonists such as Procardia, Adalat, and Calan. Among the anticholesterolemics, the statins, e.g., lovastatin, provastatin and the like are notable. Famotidine and lovastatin are preferred active agents. Combinations of various types of drugs, as well as combinations of individual drugs, are contemplated. B. Processing Aids The processing aids of the invention include high molecular weight polyethylene glycols (PEG's) and/or polyethylene glycol glyceryl esters. When microspheres are made, these materials can be called "spheronization aids." By "high molecular weight polyethylene glycols (PEG)," applicants mean PEG's having molecular weights of about 3,000 to about 8,000. "PEG 4600," having an average molecular weight of about 4400 to 4800, is a preferred material. Mixtures can be used. In chemical terms, useful PEGs are those molecules having the structural formula HOCH 2 (CH 2 OCH )m CH 2 OH, wherein m is the average number of oxyethylene groups. PEG's used for this invention are those in which m is from about 0 to about 13. Useful PEGs are solids. They are discussed on pages 355-361 of the Handbook of Pharmaceutical Excipients. 2 nd ed. (1994). The polyethylene glycol glyceryl esters useful herein are selected from those containing about 30 to about 35 oxyethylene groups. Polyethylene glycol 32 glyceryl ester sold as "GELUCIRE 50/13" by Gattefosse S.A. of France is a preferred ester. Mixtures are operable. The amounts of ingredients used in the compositions are generally within those shown in the following table. II. Processes Useful processes for making the microparticles of the invention include liquiflash conditions as well as other thermoforming processes known in the art, eg., extrusion. "Liquiflash conditions" are generally those under which the material, called a feedstock, is rapidly heated just to the point at which it undergoes intraparticulate flow and partially deforms or liquifies so that it can pass through openings in a suitable spinning device. The passage of the liquiflash particles through openings is in response to centrifugal forces within the spinning head, which forces "expel" the particles, as discrete solids out of the device and into the atmosphere. The expelled materials instantly reform into particles, without the application of external shaping forces, which particles have different morphologies from those of the feedstocks. Applicants have found that one particular spinning device is highly useful in making the microspheres of the invention. In U.S. Patent 5,458,823, a spinning device is described which uses a spinning head including a base and a cover. A plurality of closely spaced heating elements are positioned between the base and cover, forming a barrier through which the material to be processed passes. In use, the head rotates and the heating elements are heated to temperatures that bring about liquiflash conditions in the materials being processed. As the spinning head rotates, the centrifugal force created by its rotation expels the material through spaces between the heating elements. The material forms discrete, generally spherical particles as it exits. The production of microspheres for use in the subject invention may be optimized by the use of a N-groove insert inside the spinner head. The insert is described in pending U.S. Patent Application Serial No. 08/874,515, filed June 13, 1997. The insert has grooves therein, which grooves have a uniform depth and width through their length, so that highly uniform discrete microspheres or other particles are produced. Using this or a similar insert, the spinning device is operated at 50 to 75 Hz, at about 10 to 25% power, and at temperatures which yield liquiflash conditions. It should be noted that "liquiflash conditions" vary with the properties of the material, or feedstock, being processed. Since the feedstocks contain many substances in varying amounts, the parameters need to yield "liquiflash conditions" for a particular mixture must be ascertained by processing small quantities or samples before processing large ones. Typically, the feedstocks contain active agent(s) and processing aids. Among the co-assigned patents and patent applications which describe the preparations of microspheres containing bio-affecting agents re: U.S. 5,458,823; U.S. 5,638,720; and U.S. SN. 08/874,215, filed June 13, 1997. III. Microparticles While particulates made using various thermoprocessing technologies are useful, microspheres described below are preferred. The microspheres or other particulates are generally solid spherical bodies of about 150 to about 250 microns mean particle diameter. It is preferred that they be produced via a direct spheronization process, such as liquiflash or other suitable techniques. However, they may be made by physically altering the size and/or shape of non-spherical particles by extrusion/spheronization or melt granulation processes. When microspheres are made by direct spheronization of compositions containing active agent(s), the fatty esters and optional emulsifiers/surfactants, the fatty esters function as spheronization aids. The microspheres may be used as is, i.e., in powder or sachet products for delivering active agents. Alternatively, they may be used in the production of solid, liquid (suspensions), or semi-solid (e.g., gel-like) comestible units, etc. Tablets and capsules are preferred. It is preferred that the microspheres of the invention be used in combination with excipients which have been formed into floss or matrix particles. Useful flosses are generally made from saccharide based carriers. See U.S. patents 5,622,719 and 5,587,172. Once the floss and microsphere ingredients are combined, they can be shaped into comestible units. IV. Coatings One or both of the microspheres and the dosage units can be coated or encapsulated with at least one coating. Useful coating formulations contain polymeric ingredients as well as excipients conventionally employed in such coatings. The coatings are generally used for such purposes as taste-masking, controlling release and the like. Useful taste-masking coatings can include (meth)acrylate/cellulosic polymers. Ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and polymethacrylate polymers, such as Eudragit RS, Eudragit RL or mixtures thereof are useful. Preferred combinations include EC/HPC and Eudragit RS/Eudragit RL. Controlled release coatings generally contain at least one of: ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and the like. The "Eudragits" designated as NE 300, RS, L 30 D, are useful. Mixtures are operable. Coating levels of about 0 to about 150% are effective, with levels of about 5% to about 30% being preferred. Coating devices include those conventionally used in pharmaceutical processing, with fluidized bed coating devices being preferred. Examples Examples I through IIC show the preparation of microspheres. Example I Microspheres were made from a composition containing: Famotidine 30% PEG 4600 65% Gelucire 50/13 5% The spheres were made by the following procedure: The PEG 4600 and Gelucire 50/13 were milled through a 40 mesh screen using a Fitzmill M5A. The milled ingredients and famotidine were blended in a high shear mixer for 3-10 minutes. The mix was processed into spheres via spinning using the 5" V- grooved head spinning device (at 65 Hz speed and 27.5% duty cycle) disclosed in U.S. SN. 08/874,215, file June 13, 1997. The microspheres were collected and sieved through a #40 mesh onto #140 mesh. Examples HA, IIB, and IIC Using procedures similar to those of Example I, microspheres are made from compositions containing: B C Lovastatin 40% 40% 30% PEG 4600 60% 0% 65% Gelucire 50/13 0% 60% 5% The microspheres are collected and used to produce capsules. Examples III and IN illustrate coating procedures. Example III Microspheres from Example I were coated with a coating solution, consisting of a 3:7 combination of Eudragit RS/Eudragit RL along with PEG 4000 as a plasticizer and talc as an anti-adherent, at 30% coating level by weight, using a Glatt GPCG-60 fluid bed coater. The coated microspheres were used to make FLASH DOSE tablets, as described in Example V, below. Example IV The microspheres of Example I were coated with a 45:55 EC/HPC polymer solution at 30% coating level by weight using an MP Νiro-1 fluid bed coater. Example V This example shows the preparation of tablets. The following ingredients were blended in a Littleford FKM 600 blender for 10 to 15 minutes: Coated famotidine microspheres (Example III) 38.52 % 0.5% ethanol treated floss* 58.53 % Mint flavor 2.00 % Syloid 244 P 0.25 % Sodium stearyl fumarate 0.50 % Acesulfame potassium 0.20% * The floss particles contained 78.25% sucrose, 11.0% sorbitol, 10.0% xylitol and 0.75% TWEEN and were made using the procedure in Example IIIB of U.S. SN. 08/915,968, filed August 20, 1997. They were then sprayed with 0.5% ethanol by weight and dried. The ingredients were mixed and compressed on a Kilian rotary press using 9mm flat faced radial edge tooling to a tablet weight of 225.0 mg, 1.0 lb. hardness, equivalent to 20 mg famotidine dose; or using 12mm flat faced radial edge tooling to a tablet weight of 450 mg, 1.0-1.5 lb hardness, equivalent to 40 mg famotidine dose. Comestible Units The microparticles of the invention can be used in the preparation of comestible units for delivery via a variety of routes, including oral, transdermal, nasal, topical, buccal, anal and the like. Solid, liquid and semi-solid products can be made. Tablets and capsules are preferred dosage forms. Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.

Claims: We claim: 1. A composition useful in the production of thermoformed microparticles comprising: (a) about 10% to about 50% of at least one bio-affecting agent, and (b) about 50% to about 90% of at least one processing aid selected from the group consisting of (i) a high molecular weight polyethylene glycol and (ii) a polyethylene glycol glyceryl ester. 2. The composition of claim 1 wherein (b) contains both (i) and (ii). 3. The composition of claim 2 wherein the microparticles are microspheres and the bioaffecting agent is famotidine or lovastatin. 4. A process for producing microparticles comprising the steps: (1) mixing at least one bioaffecting agent with at least one processing aid selected from the group consisting of: (i) a high molecular weight polyethylene glycol and (ii) a polyethylene glycol glyceryl ester; (2) subjecting the mixture of step (1) to thermoforming conditions to produce microparticles; and (3) recovering the microparticles of step (2). 5. The process of claim 4 wherein the processing aid contains both (i) and (ii). 6. The process of claim 5, including the added step of coating the microparticles of step (3). 7. The process of claim 6 wherein the microparticles are microspheres and the bioaffecting agent is famotidine or lovastatin. 8. Microparticles produced using the process of claim 5. 9. Microparticles produced using the process of claim 6. 0. A comestible unit containing the microparticles of claim 9.

Inventors: HERMAN MARK R, MONTWILL BARBARA, PEREIRA DESIREE, SANGHVI PRADEEPKUMAR P, HERMAN, MARK, R., MONTWILL, BARBARA, PEREIRA, DESIREE, SANGHVI, PRADEEPKUMAR, P.
Applicants: FUISZ TECHNOLOGIES LTD, FUISZ TECHNOLOGIES LTD.
Application year: 1999
Main classification: A61K9
IPC codes: A61K9, A61K31