||||||||||I||US005322694A United States Patent (19) 11 Patent Number: 5,322,694 Sixsmith 45) Date of Patent: Jun. 21, 1994 (54) PHARMACEUTICAL LOZENGES 75 Inventor: David G. Sixsmith, Farnham, FOREIGN PATENT DOCUMENTS England 01.00157 7/1983 European Pat. Off. 0409279 7/1990 European Pat. Off. 73) Assignee: Merrell Dow Pharmaceuticals Inc., 2009597 6/1978 United Kingdom. Cincinnati, Ohio OTHER PUBLICATIONS (21) Appl. No.: 847,856 Gennaro. (1985). Remington's Pharmaceutical Sci 22 Filed: Mar. 9, 1992 ences. Mack Publishing Co., Pa. Oakenfull, D. et al. (1986). Food Hydrocolloids vol. 1, Related U.S. Application Data No. 2, pp. 163-176. 63 Continuation of Ser. No. 625,724, Dec. 10, 1990, aban Acta Pharmaceutica Fennica, vol. 87, No. 2, 1978, pp. doned. 61-73. (30) Foreign Application Priority Data Primary Examiner-Thurman K. Page Assistant Examiner-Raj Bawa Dec. 13, 1989 (GB) United Kingdom ................. 892896 Attorney, Agent, or Firm-Michael J. Sayles 51) Int. Cli................................................ A61K9/20 52 U.S. C. .................................... 424/440; 424/439; (57 ABSTRACT 424/441; 424/464; 424/465; 424/470; 424/488; The present invention is directed to gelatin treated 514/960 polyhydric alcohol compositions, their preparation, and 58) Field of Search ............... 424/440, 439, 441, 464, to pharmaceutical lozenges prepared therefrom. The 424/465, 470, 488; 514/960 pre-granulation of a polyhydric alcohol with an aque (56) References Cited ous gelatin solution prior to compression, produces U.S. PATENT DOCUMENTS lozenges having a delayed rate of dissolution. 4,624,849 11/1986 Toogood .......................... 424/78.01 6 Claims, No Drawings 5,322,694 1 2 which the bulking agent is a polyhydric alcohol. This PHARMACEUTICAL LOZENGES "polyhydric alcohol carrier" may also contain excipi ents commonly used in the preparation of sugar-free This is a continuation of application Ser. No. lozenges. Examples of such excipients include an addi 07/625,724, filed Dec. 10, 1990, now abandoned. 5 tional sugar-free diluent such as mannitol or sorbitol, The present invention is directed to polyhydric alco antiadherants such as colloidal silica, lubricants which hol based lozenges having a delayed rate of dissolution. are known in the art, and flavoring agents known in the Another aspect of the invention is directed to an inert art. polyhydric alcohol based carrier which will produce c) the terms "gelatin treated polyhydric alcohol such lozenges. Another aspect of the invention is di 10 based carrier' or "gelatin treated polyhydric alcohol' rected to a method for producing such a lozenge. should be construed as describing a composition con Lozenges or troches are pharmaceutical dosage taining a polyhydric alcohol and optionally containing forms which are used to treat disease states affecting the other pharmaceutical excipients which has been granu tissues contained within the oral cavity and throat. A lated with a gelatin solution, and optionally dried and typical lozenge or troche is composed predominantly of 15 milled to a particle size suitable for incorporation into an inert vehicle, carrier, or diluent. A medicinal agent is lozenge; interspersed within this carrier. The lozenge will slowly d) the terms "lozenge or troche' are used inter dissolve when placed in the oral cavity thereby releas changeably in this application and refer to a medicated ing the medicinal agent so that it may come in contact tablet or disk which will dissolve in the oral cavity with the tissues of the mouth and throat. These dosage 20 thereby releasing its medication for the treatment of forms are typically used to treat conditions such as tissues within this cavity; throat infections, dental plaque, halotosis, etc. e) the term "lozenge' should be construed as encom Typically the carrier material is a sugar such as su passing only those lozenges which are manufactured by crose, dextrose, etc. Recently consumers have become compression methods and; concerned about the excessive levels of sugar contained 25 f) the terms "carrier, diluent, and vehicle,' are used within their diets. This concern has caused a demand for interchangeably and refer to an inert excipient which sugar-free products, including sugar-free medications. serves primarily as the bulking agent in the lozenge. Pharmaceutical manufacturers have attempted to find Xylitol is one of the polyhydric alcohols which is alternative carrier bases in order to provide sugar-free suitable for use in the present invention. It is also the lozenges. One such alternative carrier is a polyhydric 30 preferred polyhydric alcohol. It is known in the phar alcohol such as xylitol. Polyhydric alcohols are consid maceutical arts as a sweetener. Its chemical name is ered as a viable alternative because they provide a sweet 1,2,3,4,5-pentanpentol. It also has been referred to as taste will mask the bitter taste of many medicinal agents. xylit, xilitol, xylitolo, klinit and pentapentol. This sub Lozenges made from polyhydric alcohols do suffer stance is available from numerous commercial sources, from one serious disadvantage. They dissolve very rap 35 such as, for example, Hoffman La Roche, Esai Co. Ltd., idly when placed in the oral cavity. For example a Finnsugar, and Roquette. Methods of manufacturing lozenge made from a xylitol based carrier will dissolve this substance are taught in the Handbook of Pharma completely within approximately 3 minutes of adminis ceutical Excipients, jointly published by the American tration. Other polyhydric alcohols such as sorbitol or Pharmaceutical Association and The Royal Pharma mannitol will also dissolve within 3 minutes of adminis ceutical Society of Great Britain (1986). tration. Thus the medicinal agents are released so rap Mannitol is known as an excipient. This substance's idly that a large percentage of the dose is washed into chemical name is 1,2,3,4,5,6-hexanehexol. It has been the patients alimentary canal rather than having an referred to as manite, manna sugar, and as manita. This opportunity to come in contact with the tissues of the substance is also available from numerous commercial oral cavity which are under treatment. Thus it would be 45 sources and its method of manufacture is taught in the a valuable contribution to the art to produce polyhydric Handbook of Pharmaceutical Excipients, id. alcohol based lozenges having slower rates of dissolu Sorbitol is also a well known pharmaceutical excipi tion within the oral cavity. ent. It's chemical name is 1,2,3,4,5,6,-hexanehexol. It has The present invention is directed to a polyhydric also been referred to as d-glucitol, d-sorbitol, sorbite, alcohol based carrier which will produce lozenges hav 50 and sorbol. This substance is also available from numer ing decreased rates of dissolution relative to the poly ous commercial sources and its method of manufacture hydric alcohol lozenges currently available. It has been is taught in the Handbook of Pharmaceutical Excipi discovered that if the polyhydric alcohol based carrier ents, id. is granulated with a gelatin solution, any lozenges pro The other polyhydric alcohols which may be utilized duced from this carrier will have a delayed rate of disso 55 in the present invention are maltitol, isomaltitol, malto lution within the oral cavity. It has also been discovered tritol, lactitol, a-l-glucopyranasido-1,6-mannitol, and that the dissolution rates of these lozenges can be fur A-linked-glucopyranasido-sorbitol. These compounds ther delayed if a hydrophobic lubricant is incorporated are also well known in the art as sugar-free substitutes. into the carrier at levels of at least 2 w/w%. For example, see CHEMICAL TECHNOLOGY RE As used in this application: VIEW, No. 30, Tablet Manufacture, Noyes Data Cor a) the term "polyhydric alcohol'should be construed poration, (1974) or SILESIA CONFISERIE MANUAL as describing the following substances: xylitol, manni NO. 3. They are available from numerous commercial tol, sorbitol, maltitol, isomaltitol, maltotritol, lactitol, suppliers, such as, for example, Aldrich, Finnsugar, or a-1-glucopyranasido-l,6-mannitol, and (3-linked Roquette. glucopyranasido-sorbitol. 65 As noted above, one aspect of the present invention is b) the term "polyhydric alcohol carrier" should be directed to a method for producing a gelatin treated construed as describing a diluent, carrier, or vehicle polyhydric alcohol based carrier, which after proper which is suitable for compounding into a lozenge, in compression will produce lozenges having delayed 5,322,694 3 4. rates of dissolution within the oral cavity. This result is lozenges and troches. Methods for producing lozenges by granulating the polyhydric alcohol with a gelatin and troches are well known in the art. Typically a me solution. This treatment should be carried out prior to dicinal agent, and excipients such as anti-adherants, the time at which the carrier is compounded into a flavoring agents, lubricants, etc. are dry blended with dosage form. the carrier and the mixture is then compressed in order This granulation is typically carried out in the follow to produce a lozenge or troche. More detailed descrip ing manner. The powdered polyhydric alcohol is op tions for producing troches and lozenges are taught in tionally dry blended with a dispersing agent such as Pharmaceutical Dosage Forms Vol. 1. The resulting microcrystalline cellulose. The function of the dispers lozenges will take at least 6 minutes to completely dis ing agent is to improve the distribution of the gelatin 10 solve within the oral cavity. through the powdered polyhydric alcohol. Other suit As noted above, the dissolution rate of the lozenge able dispersing agents include starches, untreated cellu can be further delayed if a hydrophobic lubricant is loses and modified celluloses. The quantity of dispers present in the lozenge at levels of at least 2 w/w% and ing agent that is utilized can vary widely. However, the more preferably at a level between 2-10 w/w%, and dispersing agent is generally present in this blend in the 15 quantity of from about 1-20 w/w% and more prefera most preferably about 3 w/w%.