Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-10-08
2001-08-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S469000, C424S472000, C424S479000
Reexamination Certificate
active
06277406
ABSTRACT:
BACKGROUND
The technology called “flash doses” produces dosage units which readily dissolve in the consumer's mouth. Tab-letting compositions using this concept have been described in U.S. Pat. Nos. 5,587,172, 5,616,344, and 5,622,719, all incorporated by reference and all assigned to Fuisz Technologies Ltd.
Dosage units, i.e., tablets, produced using “flash-dose” technology have better patient compliance than others because they dissolve so easily. However, “flash-dose” tablet mixes, prior to formation into tablets, are often difficult to handle. The mixes are partially amorphous with high cohesivity, so that they often are sticky and flow poorly in tableting devices. They tend to yield processing problems such as “bridging,” “arching” and “ratholing.”
Arching occurs when the mix forms a bridge across the mouth of a chute or other opening as material beneath the bridge continues onward. Ratholing is the propensity to flow from the middle leaving material clinging to the sides of the vessel or conduit.
There is a need for a method to modify the cohesive and adhesive nature of “flash-dose” tablet mixes and, thereby, reduce the stickiness which leads to arching, ratholing and other processing problems such as sticking and picking of tablets. This invention answers that need.
SUMMARY OF THE INVENTION
Applicants have discovered that decreasing the temperature of the partially amorphous shearform tablet mix, especially a mix containing glycerin, to a point below its glass transition temperature, while controlling the humidity to keep it low, minimizes sticking and improves the mix's flow properties. Also, the tableting procedure can be carried out at low humidity and low temperature to prevent sticking and picking problems, yielding tablets which dissolve quickly in the mouth.
Also, the invention provides a process by which the tablets' friability can be made from poorly flowing and cohesive shearform matrices which may be crystallized before tablet formation.
DETAILED DESCRIPTION OF THE INVENTION
The invention deals with processes for handling and tableting “flash-dose” tablet mixes and with dosage units made using those processes.
Unless otherwise stated, all parts stated are weight parts, based on the weight of the total composition.
The “flash-dose” tablet compositions are generally made from formulations containing a saccharide-based carrier, a bioaffecting agent and a binder. More than one of each of these can be used. In addition, the formulations also include one or more conventional excipients, i.e., fillers, lubricants, sweeteners, perfumes, effervescent agents, colorants, controlled release systems, coatings, crystallization modifiers and the like.
Typically, the ingredients, processes and devices disclosed in U.S. Pat. Nos. 5,587,172, 5,616,344, 5,622,719, and 5,637,326 are useful herein. The ingredients are those useful in making the shearform matrices, or flosses, described therein. These disclosures are hereby incorporated by reference.
The inventor deals with the use of at least one of the following techniques for improving the processability of tablet compositions:
i) storing the composition at low temperature and at controlled humidity; and
ii) molding the composition at low temperature and at low humidity. Ideally, both techniques i) and ii) are used.
Improved processability is found when the cohesion of the tablet composition (i.e., that tendency of particles to stick or adhere to each other) is greater than its adhesion (i.e., the tendency for the composition's mass to stick to surfaces during storage, handling and/or molding).
By “low temperature” applicants mean a temperature below the glass transition temperature of the formulation. Ideally, that temperature will be below the melting point of any liquid binder, e.g., glycerin, which is used in the composition. Temperatures of less than 15° C. are used, with those between about −20° C. and 10° C. being highly effective.
“Controlled humidity” means that the tablet composition is stored in closed vessels, e.g., sealed containers, or is otherwise handled to ensure that its humidity does not exceed 40% relative humidity during storage. Relative humidity values of about 10% to about 30% are optimal.
When the temperature and humidity are kept low, the cohesion/adhesion ratio is maintained. Also, when the humidity is low, the condensation of moisture on the surface of the mix or on equipment is eliminated.
The feedstock for making shearform matrices includes a carrier which is capable of undergoing the physical and chemical changes associated with flash-flow processing. These carriers are carbohydrates, with saccharide-based materials being very effective.
Sugars, i.e., sucrose, fructose, lactose, and sugar alcohols, e.g., sorbitol, monitol, xylitol and the like, are useful feedstocks. Combinations of C
5
to C
6
sugars and sugar alcohols can be used, as well as mixtures containing mono-, di- and poly-saccharides and other suitable carriers.
During processing, the saccharide-based carriers are subjected to heat and optional shear forces sufficient to change their morphological properties and yield amorphous matrices.
The bioaffecting agents useful include a wide variety of substances. Among them are those in the following therapeutic categories: ace-inhibitors, analgesics, antacids, anti-anginal drugs, anti-arrhythmia agents, antiasthmatics, anticholesterolemics, anticonvulsants, antidepressants, antidiarrheal preparations, antihistamines, antihypertensives, anti-infectives, anti-inflammatories, antilipid agents, antimaniacs, antinauseants, antistroke agents, antithyroid preparations, anabolic drugs, antiparasitics, antipsychotics, antipyretics, antispasmodics, antithrombotics, 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, erthropoietic drugs, expectorants, fertility agents, fungicides, gastrointestinal agents, growth regulators, H
2
-antagonists, hormone replacement agents, hyperglycemic agents, 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, steroids, stimulants, sympatholytics, thyroid preparations, tranquilizers, uterine relaxants, vaginal preparations, vasoconstrictors, vertigo agents, vitamins, wound healing agents, and others.
Highly useful bioaffecting agents include analgesics, H
2
-antagonists and antacids. Analgesics such as aspirin, acetaminophen and acetaminophen plus caffeine may be processed in accordance herewith.
H
2
-antagonists contemplated include cimetidine, ranitidine, famotidine, rizatidine, ebratidine, mefintidine, roxatidine, pisotidine, aceroxatidine and their salts.
Antacids can be prepared from ingredients such as: aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodium carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate, calcium phosphate, citrate ion (acid or salt), amino acetic acid, hydrate of magnesium aluminum sulfate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, aluminum mono- or di-basic calcium phosphate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicates, tartaric acids and salts, and the like. Mixtures are operable. Moreover, antacids can be used in combination with H
2
-antagonists.
Other useful bioaffecting ingredients include antidiarrheals such as IMMODIUM AD
Fuisz Richard C.
Misra Tushar K.
Sanghvi Pradeepkumar P.
Channavajjala Lakshmi
Fuisz Technologies Ltd.
Levis John F.
Page Thurman K.
Schmidt Richard D.
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