Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3870790 A
Publication typeGrant
Publication dateMar 11, 1975
Filing dateOct 25, 1972
Priority dateJan 22, 1970
Publication numberUS 3870790 A, US 3870790A, US-A-3870790, US3870790 A, US3870790A
InventorsLowey Hans, Stafford Herbert Henry
Original AssigneeForest Laboratories
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose
US 3870790 A
Abstract
A solid pharmaceutical composition in which the carrier consists essentially of hydroxypropylmethylcellulose, or hydroxypropylmethylcellulose admixed with up to about 20% ethylcellulose, is prepared by compressing a mixture comprising one therapeutic agent and the hydroxypropylmethylcellulose powder which has been humidified to a moisture content of from about 5 to about 25% by weight at a low compression pressure. The solid pharmaceutical composition obtained will release the active ingredient contained therein evenly over a prolonged period, e.g. from about 1 to 8 hours.
Images(8)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent [191 Lowey et al.

[ Mar. 11, 1975 SOLID PHARMACEUTICAL FORMULATIONS CONTAINING HYDROXYPROPYL METHYL CELLULOSE [75] Inventors: Hans Lowey, Mamaroneck; Herbert Henry Stafford, Staten lsland, both of N.Y.

[73] Assignee: Forest Laboratories, Inc., New

York, NY.

[22] Filed: Oct. 25, 1972 [21] Appl. No.: 300,745

Related U.S. Application Data [63] Continuation-in-part of Ser. No. 5,140, Jan. 22, 1970, abandoned, which is a continuation-in-part of Ser. No. 626.968, March 30, 1967, abandoned.

[56] References Cited UNITED STATES PATENTS 2,887,440 5/1959 Grcminger et a1 424/362 X 2,949,401 8/1960 Wershaw 424/362 X 3,181,998 5/1965 Kanig Cyr ct a1. Nurnbcrg 424/238 X Primary Examiner-Albert T. Meyers Assistant E.raminer-Leonard Schenkman [57] ABSTRACT A solid pharmaceutical composition in which the carrier consists essentially of hydroxypropylmethylcellulose, or hydroxypropylmethylcellulose admixed with up to about 20% ethylcellulose, is prepared by compressing a mixture comprising one therapeutic agent and the hydroxypropylmethylcellulose powder which has been humidified to a moisture content of from about 5 to about 25% by weight at a low compression pressure. The solid pharmaceutical composition obtained will release the active ingredient contained therein evenly over a prolonged period, e.g. from about 1 to 8 hours.

3 Claims, No Drawings SOLID PHARMACEUTICAL FORMULATIONS CONTAINING HYDROXYPROPYL METHYL CELLULOSE CROSS-REFERENCE This is a continuation-in-part of U.S. application Ser. No. 5,140, filed Jan. 22, 1970 now abandoned, which, in turn, is a continuation-in-part of U.S. application Ser. No. 626,968, filed Mar. 30, 1967, now abandoned.

DETAILED DESCRIPTION Sustained release products of conventional character are well known to the art and have been found to have a number of advantages. Specifically, the release of the medication contained therein is uniform and continuous over a period of time, thereby avoiding the necessity of frequent administration of the medicament while at the same time achieving a desired blood level of active ingredient. The preparation of sustained release compositions often requires a rather substantial and complicated procedure and often the degree ofpredictability and the release pattern are less than optimum.

The use of cellulose derivatives such as hydroxypropylmethylcellulose as an ingredient in pharmacetical formulations is of course known. Thus U.S. Pat. No. 3,266,992 describes the incorporation of up to 30% of various cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose and hydroxyethylcellulose, the particular derivative depending upon the nature of the therapeutic agent, into tablets to effect rapid disintegration thereof. U.S. Pat. No. 2,887,440 on the other hand discloses the use of hydroxypropylmethylcellulose in enteric coatings to prevent disintegration of the tablet core. It has also been recognized that methylcellulose might itself be a desirable material for certain pharmaceutical formulations but attempts at achieving such products have not met with success. Thus U.S. Pat. No. 2,949,401 recognizes the desirable properties of methylcellulose in a buccal tablet containing vitamin A but limits the amount to from 3 to 5%. Trotter and coworkers report several unsuccessful attempts at directly compressing methylcellulose into a troche and succeeded only by incorporating 25% superfine sugar with the methylcellulose. Amer. Jour. Pharm, February 1956, pp. 5056. The combination of cellulose derivatives with large amounts of lactose is also described in U.S. Pat. No. 3,344,030. U.S. Pat. No. 3,590,117 reports the unsatisfactory nature of hydroxypropylmethylcellulose for troches. U.S. Pat. No. 3,312,594 describes troches containing carboxymethylcellulose but only in combination with equal amounts of pectin and gelatin.

The present invention relates to a long-acting sustained dosage unit, and the carriers and active ingredients in the composition thereof, presented in a solid coherent form. The long-acting dosage unit contains at least one active ingredient compressed with a mixture containing a moisturized carrier consisting esentially of 100 to 80% by weight of hydroxypropylmethylcellulose and optionally 0 to 20% by weight of ethylcellulose. The carrier ingredient during use gradually releases the active ingredient by contact with fluids, such as saliva, gastric juices, and other natural secretions and does so over an extended period, e.g., about 1 to 8 hours. In one aspect the invention comprises a long-acting troche, lozenge or tablet. The solid pharmaceutical form according to the present invention can however be utilized in other routes of administration in addition to buccal. Thus the solid form may be administered orally as a tablet to be swallowed or rectally or vaginally as a suppository.

Specifically, the carrier is hydroxypropylmethylcellulose which has been humidified under controlled conditions to a moisture content of from about 5 to about 25% by weight. This material, optionally containing ethylcellulose, can then be compressed at a low pressure, e.g. only 5 to 8 pounds per square inch, which, because of the moisture content, is sufficient to shape the material into a solid coherent pharmaceutical form such as a troche to be sucked or used in the oral cavity so as to effect a gradual release of the active therapeutic ingredient which is absorbed through the oral mucosa through the blood stream. Higher degrees of compression, e.g., up to about pounds per square inch, yield a harder and more long lasting composition as might be desired for example in a suppository to be inserted in the rectum or vagina, or a tablet to be simply swallowed.

According to the present invention it has now been found that a reliable and effective long acting sustained action solid dosage unit can be very simply made by compressing an appropriate amount of practically any desired active ingredient or medicament with a premoisturized hydroxypropylmethylcellulose powder or with a mixture of a combination of moisturized hydroxypropylmethylcellulose and ethylcellulose powder. The release time, the dosage unit and pattern of release can be controlled by the relative amounts of hydroxypropylmethylcellulose and ethylcellulose employed, the size and weight of the tablet product, the degree of compression or a combination thereof, bearing in mind that a high degree of moisturization permits the use of low compression pressures, and visa versa, for the blend of active ingredient and cellulose powder and that increased compression increases the compositions span of action. It is thus an important feature of the present invention that a sustained release product can be readily and easily prepared containing, as the sole carrier, varying amounts of hydroxypropylmethylcellulose and ethylcellulose having a predetermined moisture content and that by controlled variation of the moisture content of the alkylated cellulose carrier pow der, the duration of the release period of the active medicament held in the compacted tablet may be controlled. The release of the active ingredient is, therefore, controlled by the size and the weight, moisture content and degree of compression pressure exercised on the lozenge, suppository or tablet at the time it is being formed from the pre-wetted powder and active medicament.

In general, the long acting carrier products of the present invention are produced by combining the appropriate amount of active ingredient into the shape of troches, lozenges, tablets or suppositories with a mixture of from about -80% by weight of hydroxypropylmethylcellulose and from about 020% by weight of ethylcellulose. The product can also contain adjuvants such as a synthetic sweetening agent as for example saccharin, a nontoxic food grade color such as FD&C Yellow No. 10, a flavoring agent such as cherry flavor and a preservative such as pmethylbenzoic acid. The only criterion for the addition of such materials is that they do not tend to dehydrate the product before or after it is tableted by compression techniques.

Specific techniques for the manufacture and use of the long acting carrier will be set forth in greater detail below but an illustration of the improved activity of the product may briefly be noted by the following illustration. For example, a grain lozenge when held in the mouth will release its active ingredient in a regular manner over a period of one and one-and-one-half hours by dissolution or disintegration of the lozenge by the saliva fluids. If the same lozenge is inserted in the upper cavity of the mouth, the release then can be extended to 3 hours. Moreover a shaped product or tablet of the present invention which has a weight of about grains is noted to take almost twice as long to release its active ingredient as a 5 grain product.

When used as a lozenge, release through the action of the saliva is continuous and the active ingredient then passes through the gastro-intestinal tract into the blood stream. However, when the composition is positioned in the buccal pouch, absorption of the active ingredient takes place through the mucosa membrane lining the pouch directly through the capillaries in the blood stream.

A similar pattern can be observed when the solid pharamaceutical form takes the form of a suppository. Here again the exclusive carrier has highly desirable properties in that it is non-irritating, substantially neutral and adherent.

While the solid pharmaceutical forms of the present invention intended for oral administration; i.e., tablets to be swallowed, will be subjected to the effects of both gastric and intestinal fluids and mechanical wear within the gastrointestinal tract, a prolonged rate of release is also seen here.

The invention has flexibility and versatility dependent upon the particular nature of the active ingredient which is to be dispensed, the treatment or condition for which the active ingredient is indicated, the route of administration and the desired length of release time of the active ingredient. It has been found that one may for example prepare a 50 lb. mixture for the production of long acting troches from a composition indicated in the following Table:

TABLE No. Make of Materials Lbs. Ozs. Grs.

l 0.10% Calcium cyclamate 350 2 [00% Cherry Flavor 8 3 0.10% Methyl Paraben 350 4 0.01% Propyl Paraben 35 5 0.50% Lake Dye.Red No. 2 4 6 Mixture of 85% Methocel HG 6O 49 2 140 (20% of H 0), premium viscosity 50 and l5% Ethylcellulose N50 tions are not only permissible but are intended as these variations affect the release time and pattern of the active ingredient.

In preparing troches from the above mixture, items 1, 2, 3 and 4 are weighed out and thoroughly mixed. Item 5, which is the food grade dye, is placed in a mortar and rubbed with some of the mixture of Items 1, 2, 3 and 4 following which the remainder of Items 1, 2, 3 and 4 is added and the rubbing is conducted until a homogenous blend is obtained. Item 6, which is the specifled cellulose powder mixture, is added to the previously produced mixtures of Items 1, 2, 3, 4 and 5 and the entire composition is blended until uniformity is achieved. The uniform dry mixture of ingredients is then spread out on trays and thoroughly sprayed with a 35% mixture of ethanol and distilled water. The thus treated mixture is allowed to dry overnight and is then ground on a Fitzpatrick mill to an average 2040 mesh particle size. The powder derived from the Fitzpatrick mill is next placed on trays which trays are put into a steam room and held there overnight under conditions of very high humidity for the express purpose of creating in the previously dry blend, certain moisture levels which are important in the ultimate performance of each tablet in simultaneously maintaining its integrity and sustained even release of active ingredient. As a means of maintaining the desired humidity at a fixed level in the powder, trays filled with water are placed in the steam room to maintain the even consistency of the humidity level to insure adequate wetting of the powder. The room temperature is about F and humidity is maintained between about 78 to 82% for 24 hours (overnight). The resulting material will have a moisture content from about 20 to about 25% by weight.

After a constant moisture level is thus achieved, the active ingredient is added and the entire batch of material is placed in the hopper of a conventional tableting machine which is set up with half-inch punches and dies and the machine is adjusted and regulated for 8 pounds of pressure per square inch and for product size. In this manner, 7 /2 grain or 10 grain tablets preferably, are produced and by following the same procedure, but suitably further adjusting the machine, 12 grain or other size tablets are produced.

Alternatively, the procedure is carried out by introducing the hydroxypropylmethylcellulose or a mixture of the hydroxypropylmethylcellulose with ethylcellulose into an oven chamber having an exhaust aperture whichis at that time in closed or shut position. The chamber is provided with a heating unit and a forced air blower, which is inoperative at this stage of the procedure, the heat and forced air being applied at a subsequent stage. The material to be processed is placed in thin layers (not more than inch thick) on trays of the oven chamber which are lined with heat-resistant parchment paper and the trays are placed on racks in the oven chamber using only alternate shelves, thereby providing a predetermined amount of spacing between the layers of material being treated. There is then placed within the oven chamber a humidifier equipped with a humidistat which is pre-set to maintain humidity in the oven chamber at 85 the humidifier being filled with sufficient distilled or deionized water to last for 24 to 36 hours. The humidifier is now activated and the oven chamber is closed and the process is allowed to proceed under the 85 90% humidity for a minimum of 24 hours. Humidification can be continued for up to 36 hours or even longer if desired, although there is no special advantage in exceeding 36 hours and unduly extended times are apt to be uneconomical, but the treatment should be continued at least about 24 hours. The humidifier is then removed from the oven chamber, the exhaust aperture opened by manipulation of the valve and the forced air blower is activated thereby applying heat at a controlled temperature in the range of 100 to 120F (43 to 49C). The moisture content will then decrease, depending upon the length of time the mate rial is treated with the hot air. At the end of 12 hours for example the moisture content of the treated material is at its lowest limit of the range, about 5%. This is not an exact limit since this added moisture content can be as low as 4 or 4 6%, as determined by a standard moisture determination apparatus. The 12-hour period just referred to is also approximate as the duration of the period may vary somewhat above or below 12 hours, but it has been found in practice that the period should not exceed approximately 12 hours.

When the required added moisture content is achieved, the treated material is removed from the oven and passed through a No. 2 stainless steel screen employing a Fitzpatrick mill and processed as described above.

Variations in the two extremes are of course readily apparent, the critical factor being that the hydroxypropylmethylcellulose is so treated that its moisture content is stabilized at a higher level than is normally encountered.

The hydroxypropylmethylcellulose preferably employed is identified as Methocel HG 60 which is a commercial methylcellulose product manufactured by the Dow Chemical Company, Midland, Michigan and has a methoxyl percentage of 28 to 30%, a hydroxypropoxyl percentage of 7 to 12%, is soluble in water and organic solvents, has a normal gel temperature of 60F and demonstrates an average viscosity of 50 centipoises (range 40 to 60, 2% aqueous solution).

As regards the ethylcellulose, this material corresponds to that defined in the National Formulary XIII with a standard ethoxy content ranging between 44.0 and 51.0%, preferably 4849..5%, by weight. The preferred material corresponds to ethylcellulose N50, the number N50 indicating the viscosity in centipoises of a 5% by weight solution of the product in a 80/20 toluene/ethanol solvent at a temperature of 25C. These viscosity numbers are indicative of the size of the ethylcellulose molecules, the larger the molecule, the greater the viscosity and can be further referred to in the standard charts on the products which are readily available.

The active ingredient may be of any suitable nature such as insulin, vitamins, hormones, analgesics, local anesthetics, epinephrine, antiinflammatory steroids, progestational agents, antibiotics, antiseptics, antimycotics, antacids and the like. The nature of the therapeutic agent is not critical and any drug, or stable combination of drugs, can be incorporated into these novel pharmaceutical forms. This is particularly important since some active medicaments such as insulin, antidiuretic hormones and epinephrine become inactivated when incorporated into conventional or previously known sustained release products where the products are swallowed and the release occurs in the gastric fluids or in the intestinal fluids or in a combination of both. Some active agents such as ACTH, epinephrine, vitamin B iron insulin, antidiuretic hormones, prednisolone and nitroglycerine as well as antiobesity agents and antacids can, in accordance with the present invention, be administered via the transmucosal absorption route. However those therapuetic agents which are active when swallowed, can also be administered in the new pharmaceutical carrier of the present invention, the composition being used exactly like a conventional tablet. Similarly, antimicrobial agents such as furazolidone and nifuroxime can be administered in a vaginal suppository. Products of the present invention are also useful as demulcents in the treatment of painful ulcerations, inflammations, and irritations. These effects have been shown by in vitro and in vivo clinical tests.

Moreover, it can be shown by X-ray studies a tablet prepared according to the present invention for very long release, while gradually dissolving remains coherent for most of its passage through the gastro-intestinal tract. Hence a tablet of the moisturized hydroxypropylmethylcellulose and barium sulfate (as an X-ray contrast agent) having a total weight of 600 mg, a diameter of 12.7 mm, a thickness of 3.15 mm and a hardness of 6.6 lbs/in can still be seen in X-rays for more than 5 hours after administration. A typical progression is as follows:

1 hr. small intestine 1 hr. 35 min. do.

2 hr. 20 min. do.

5 hr. 10 min. caecum Since the therapeutic agent is being continuously released, the observed period of activity will be even longer than this.

The invention is further illustrated by the following non-limitative examples:

EXAMPLES l-ll SUSTAINED RELEASE TROCHE FORMULATIONS 50 LB. MIXTURE FOR 50,000 TABLETS AT 7 GRAINS EXAMPLE 1 PREDNISOLONE, 4 MG.

No. Make of Materials Lbs. Ozs. Grs.

l. Prednisolone 7 60 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 6O 48 l l hydroxypropylmethylcellulose,

premium, viscosity 50,

moisture 20% by weight EXAMPLE 2 EPINEPHRINE, 1 MG No. Make of Materials Lbs. Ozs. Grs.

l. Epinephrine l 330 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 49 245 EXAMPLE 2-C0ntinued EXAMPLE 7 EPIN EPHRINE, 1 MG No. Make of Materials Lbs. Ozs. Grs.

hydroxypropylmethylcellulose, premium,viscosity O moisture 20% by weight EXAMPLE 3 DIBUCAINE, 3 MG No. Make of Materials 1 L Ozs. Grs.

1. Dibucaine 5 I50 2. 0.10% Calcium cyclamate 350 3. 100% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 48 12 440 hydroxypropylmethylcellulose premium,viscosity 5O moisture 20% by weight EXAMPLE 4 BENZOCAINE, 20 MG No. Make of Materials Lbs. Ozs. Grs.

1. Benzocaine 2 3 300 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 46 14 290 hydroxypropylmethylcellulose premium, viscosity 50 moisture 20% by weight EXAMPLE 5 TRIAMCINOLONE ACETONIDE, 0.25 MG No. Make of Materials Lbs. Ozs. Grs

1. Triamcinolone Acetonide 188 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 49 1 402 hydroxypropylmethylcellulose premium, viscosity 50 moisture 20% by weight EXAMPLE 6 HEPARIN, 50 MG No. Make of Materials Lbs. Ozs. Grs.

1. Heparin 5 8 165 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 6O 35 5 210 hydroxypropylmethylcellulose premium, viscosity 50, moisture 20% by weight 8. Ethocel N50 ethylcellulose 9 2 70 VITAMIN B12, 1000 MCG No. Make of Materials Lbs. 07s. Grs.

1. Vitamin B 1 330 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 41 10 hydroxypropylmethylcelluose premium, viscosity 50 moisture 20% by weight 8. Ethocel N50 ethylcellulose 8 3 345 EXAMPLE 8 INSULIN, 250 INT. UNITS No. Make of Materials Lbs. Ozs. Grs.

l. Insulin 1 330 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 3S 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 hydroxypropylmethylcellulose, premium, viscosity 50 moisture 20% by weight EXAMPLE 9 SODIUM BICARBONATE, 0.3 GM GRAIN TABLETS No. Make of Materials Lbs. Ozs. Grs.

1. Sodium Bicarbonate 33 1 23 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 53 hydroxypropylmethylcellulose premium, viscosity 5O moisture 20% by weight 8. Ethocel N50 ethylcellulose 13 14 412 EXAMPLE l0 d-DESOXYEPHEDRINE HYDROCHLORIDE, 5 MG No. Make of Materials Lbs. Ozs. Grs.

1. d-Desoxyephedrine Hydrochloride 8 390 2. 0.10% Calcium Cyclamate 350 3. 1.00% Cherry Flavor 8 4. 0.10% Methyl Paraben 350 5. 0.01% Propyl Paraben 35 6. 0.50% Lake Dye Red No. 2 4 7. Methocel HG 60 49 7 45 hydroxypropylmethylcellulose, premium, viscosity 50 moisture 20% by weight In examples 1 10, the calcium cyclamate can be replaced by 0.1 the amount of sodium saccharin while the Lake Dye Red No. 2 can be replaced by another pharmaceutically acceptable coloring agent or omitted altogether from the formulation.

EXAMPLE ll REPRESENTATIVE RELEASE PATTERNS 260 individual tests have been made on 31 subjects with both lozenges and tablets inserted either in the buccal pouch on held sublingually, and show the following results:

LOZENGES Partial dissolution time Medium range per 1/10 gram carrier, 15.8 to 21.5 minutes. Medium range per 7 grain lozenge, 81 to 108 minutes. Medium range per 14 grain tablet, 158 to 215 minutes.

2. Total dissolution time.

3. Total dissolution time.

TABLETS INSERTED IN BUCCAL POUCH OR USED SUBLINGUALLY 1. Partial dissolution time. Medium range per 1/10 gram carrier, 29.4 to 42.1 minutes. Medium range per 7 grain tablet, 149 to 212 minutes. Medium range per 14 grain tablet, 294 to 421 minutes.

2. Total dissolution time.

3. Total dissolution time.

EXAMPLE 12 Analgesic Tablet Ingredients mg/tablet 1 Aspirin powder U.S.P. 525.0 2 Methocel HG 60 hydroxypropylmethylcellulose,

premium, viscosity 50, moisture 5% by weight 325.5 3. Glycine 45.0 4. Syloid 244 micron size silica 4.5

Ingredients 1, 2 and 3 are mixed in a bowl into which ingredient 4 is added after screening and the whole blended for 20 minutes and compressed in a tableting machine having a one-half inch die size and a one-half inch punch to make tablets with an average weight of 0.9 g and a thickness of 0.210 t 0.01 inch. The hardness of the tablet was 2228.6 lbs/square inch.

EXAMPLE l3 Antihistamine Tablet Ingredients mg/tablet l Chlorpheniramine maleate U.S.P. 12.60 2 Methocel HG 60 509.20

hydroxypropylmethylcellulose, premium. viscosity 50, moisture 4%% bylweight 3 Methyl paraben .S.P 0.52 4 Propyl faraben U.S.P. 0.06 5 Syloid 44 micron size silica 2.63

Ingredient 2 was placed in a container and ingredients l. 3, 4 and 5 were weighed out and added after screening and the whole blended for 20 minutes. The compression into tablets was conducted on a tableting machine using a die size of seven-sixteenths inch with a pound of seven-sixteenths inch to obtain a. tablet thickness of 0.250 t 0.01 inch with a tablet hardness of 2228.6 lbs/square inch. Each tablet weighed 0.525

3, 4 and 5 and the whole blended for 20 minutes and compressed as in Example 13. The tablet thickness was 0.250 $0.01 inch and the hardness was 22.2 lbs/square inch. Each tablet weighed 0.55 g.

EXAMPLE 15 Laxative Tablet Ingredients mg/tablet 1 Phenolphthalein U.S.P. 66.0 2 Methocel HG 60 480.64

hydroxypropylmethylcellulose,

premium, viscosity 50,

moisture 4% by weight 3 Methyl paraben U.S.P. 0.55 4 Propylgaraben U.S.P. 0.06 5 Syloid 44 2.75

The same procedure was followed as in Example 13 with the same results.

EXAMPLE 16 Vitamin Tablet Ingredients mg/tahlet Ascorbic acid, U.S.P., powder Methocel HG 60 hydroxypropylmethylcellulose, premium, viscosity 50, moisture 5% by weight 3 Syloid 244 g 4 Ingredients 1 and 2 were weighed out as in the preceding examples and placed into a stainless steel bowl into which ingredient 3 was added after screening and the whole blended for 20 minutes and compressed as previously described. The tablets had a thickness of 0.210 t 0.01 inch and a hardness of 22.2-28.6 lbs/square inch. Each tablet weighed 0.8 g.

EXAMPLE 17 Ingredients Amount/Suppository l Furazolidone 0.005 g 2 Nifuroxime 0.007 g 3 Methocel HG 60 1.988 g hydroxypropylmethylcellulose,

premium, viscosity 5 moisture 7.5% by weight The ingredients are thoroughly mixed and compressed in a similar fashion to that described above utilizing however a suppository mold to yield a vaginal suppository weighing 2 g.

The above ingredients are mixed and thoroughly blended for minutes and then compressed to for rectal suppositories of 1.14 g each.

What is claimed is:

l. A method of preparing a long-acting compressed buccal composition for the administration of transmucosally absorbed therapeutic agents consisting essentially of the therapeutic agent and a carrier which comprises subjecting an effective amount of a dry carrier consisting of from to of hydroxypropyl methyl cellulose having a methoxyl content of 28 to 30% and a hydroxypropyl content of 7 to 12% and from 20 to 0% of ethyl cellulose having an ethoxy content of 48 to 49.5% to controlled humidity for a time sufficient to establish a moisture content of from about 5 to about 25%, mixing the moisturized carrier with a therapeutically effective amount of the therapeutic agent and compressing the mixture into solid shaped units at a pressure of from about 5 to about 8 pounds per square inch.

2. The product prepared by the process of claim 1.

3. The product of claim 1 which additionally contains a synthetic sweetening agent, a coloring agent, a flavoring agent and a preservative.

UNITED STATES PATENT AND TRADEMARK OFFICE @ETTTTQATE PATENT NO. 3 870,,790 DATED Mamh 9 1975 iN\/ ENTOR(S) Hans Lowey 5: Herbert Henry Stafford It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Examples 6 7 and 9, the last line of each should read N50 Ethyleellulose by deleting "Ethocel".

' win. me we ismei a eom e. mm c. mesmu: ANN

Anminfi QT/RW v Commissioner oj'Parems and Trademarks

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2887440 *Aug 12, 1957May 19, 1959Dow Chemical CoEnteric coating
US2949401 *Jul 28, 1958Aug 16, 1960Dome Chemicals IncBuccal tablet containing vitamin a
US3181998 *Aug 12, 1960May 4, 1965Kanig Joseph LTablet disintegration
US3312594 *Jun 21, 1963Apr 4, 1967Squibb & Sons IncLonglasting troche
US3424842 *May 4, 1965Jan 28, 1969Merck Ag EManufacture of tablets directly from dry powders
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3976764 *Mar 11, 1975Aug 24, 1976Eisai Co., Ltd.Solid therapeutic preparation remaining in stomach
US4163777 *Apr 29, 1977Aug 7, 1979Lewis/Howe CompanyControlled antacid delivery form and method of treatment therewith
US4183898 *May 25, 1978Jan 15, 1980Liff Lawrence JLiquid base makeup composition
US4188188 *Sep 27, 1978Feb 12, 1980Bio-Rad Laboratories, Inc.High density lipoprotein cholesterol assay
US4226849 *Jun 14, 1979Oct 7, 1980Forest Laboratories Inc.Sustained release therapeutic compositions
US4259314 *Dec 10, 1979Mar 31, 1981Hans LoweyMethod and composition for the preparation of controlled long-acting pharmaceuticals
US4292300 *Jul 20, 1977Sep 29, 1981Inveresk Research InternationalControlled release suppositories
US4349535 *Jan 11, 1980Sep 14, 1982Liff Lawrence JLiquid base makeup composition
US4357469 *Jun 29, 1981Nov 2, 1982Forest Laboratories, Inc.Carrier base material for prolonged release therapeutic compositions
US4369172 *Dec 18, 1981Jan 18, 1983Forest Laboratories Inc.Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4389393 *Mar 26, 1982Jun 21, 1983Forest Laboratories, Inc.Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
US4432975 *Oct 19, 1981Feb 21, 1984Icn Pharmaceuticals, Inc.Process for introducing vitamin B-12 into the bloodstream
US4465660 *Dec 21, 1982Aug 14, 1984Mead Johnson & CompanySustained release tablet containing at least 95 percent theophylline
US4529589 *Sep 29, 1983Jul 16, 1985Davydov Anatoly BPharmaceutical composition for the treatment of diabetes mellitus
US4540566 *Apr 2, 1984Sep 10, 1985Forest Laboratories, Inc.Prolonged release drug dosage forms based on modified low viscosity grade hydroxypropylmethylcellulose
US4547358 *Jun 4, 1984Oct 15, 1985Mead Johnson & CompanySustained release tablet containing at least 95 percent theophylline
US4647599 *Nov 9, 1984Mar 3, 1987Egyt Gyogyszervegyeszeti CyarSustained release pharmaceutical tablets and process for the preparation thereof
US4668517 *Apr 4, 1985May 26, 1987Norwich Eaton Pharmaceuticals, Inc.Furazolidone dosage form
US4680323 *Dec 1, 1983Jul 14, 1987Hans LoweyMethod and composition for the preparation of controlled long-acting pharmaceuticals for oral administration
US4695591 *Nov 22, 1985Sep 22, 1987Schering CorporationControlled release dosage forms comprising hydroxypropylmethylcellulose
US4713239 *Nov 19, 1985Dec 15, 1987Vsesojuny Kardiologichesky Nauchny Tsentr Adkaemii Meditsinski Nauk SssrAntianginal film and method of treating ischemic heart disease
US4764378 *Feb 10, 1986Aug 16, 1988Zetachron, Inc.Buccal drug dosage form
US4775535 *Apr 4, 1986Oct 4, 1988Hans LoweyMethod of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics
US4786503 *Apr 6, 1987Nov 22, 1988Alza CorporationDosage form comprising parallel lamine
US4803079 *Dec 20, 1985Feb 7, 1989Syntex (U.S.A.) Inc.Controlled release naproxen and naproxen sodium tablets
US4842854 *May 13, 1987Jun 27, 1989Vsesojuzny Kardiologichesky Nauchny Tsentr Akademii Meditsinskiki Nauk SsrAntianginal plate for treating ischemic heart disease
US4851232 *Jun 8, 1987Jul 25, 1989Alza CorporationDrug delivery system with means for obtaining desirable in vivo release rate pattern
US4855143 *Jul 12, 1988Aug 8, 1989Hans LoweyMethod of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics
US4880830 *Feb 9, 1987Nov 14, 1989Ethical Pharmaceuticals LimitedSlow release formulation
US4921695 *Mar 9, 1989May 1, 1990Babaian Eduard AAntianginal plate for treating ischemic heart disease
US4942040 *Sep 29, 1988Jul 17, 1990Aktiebolaget HasslePharmaceutical preparation and a process for its preparation
US4946685 *Sep 1, 1988Aug 7, 1990Alza CorporationCellulosic dosage form
US4950484 *Mar 2, 1988Aug 21, 1990Gist-Brocades N.V.Pharmaceutical tablet, pharmaceutical granulate and process for their preparation
US4983398 *Dec 15, 1988Jan 8, 1991Forest Laboratories, Inc.Sustained release drug dosage forms containing hydroxypropylmethylcellulose and alkali metal carboxylates
US5028633 *Feb 21, 1985Jul 2, 1991Freund Industrial Co., Ltd.Excipient for use in compression molding and process of preparation
US5126145 *Jun 11, 1990Jun 30, 1992Upsher Smith Laboratories IncControlled release tablet containing water soluble medicament
US5204116 *May 1, 1991Apr 20, 1993Alza CorporationDosage form providing immediate therapy followed by prolonged therapy
US5268181 *Jun 29, 1992Dec 7, 1993Upsher-Smith Laboratories, Inc.Method of using niacin to control nocturnal cholesterol synthesis
US5292518 *Mar 16, 1992Mar 8, 1994Hauser-KuhrtsProlonged-release drug tablet formulations
US5338550 *Dec 21, 1992Aug 16, 1994Alza CorporationStereoisomer therapy
US5393765 *Dec 13, 1993Feb 28, 1995Hoffmann-La Roche Inc.Pharmaceutical compositions with constant erosion volume for zero order controlled release
US5403593 *Mar 31, 1992Apr 4, 1995Sandoz Ltd.Melt granulated compositions for preparing sustained release dosage forms
US5436009 *Dec 15, 1992Jul 25, 1995Dagra Pharma B.V.Sustained release suppositories and a process for preparation
US5472712 *Jun 23, 1993Dec 5, 1995Euroceltique, S.A.Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US5478572 *Sep 6, 1994Dec 26, 1995Bristol-Myers Squibb Co.Gepirone dosage form
US5484607 *Oct 13, 1993Jan 16, 1996Horacek; H. JosephExtended release clonidine formulation
US5672360 *Nov 22, 1994Sep 30, 1997Purdue Pharma, L.P.Method of treating pain by administering 24 hour oral opioid formulations
US5681585 *Jun 20, 1996Oct 28, 1997Euro-Celtique, S.A.Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5869100 *Jun 24, 1997Feb 9, 1999Horacek; H. JosephExtended release clonidine formulation (tablet)
US5879705 *Apr 18, 1997Mar 9, 1999Euro-Celtique S.A.Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
US5948437 *May 28, 1997Sep 7, 1999Zeneca LimitedPharmaceutical compositions using thiazepine
US5958459 *Nov 27, 1995Sep 28, 1999Purdue Pharma L.P.Opioid formulations having extended controlled released
US5968551 *Jul 27, 1995Oct 19, 1999Purdue Pharma L.P.Orally administrable opioid formulations having extended duration of effect
US6010718 *Apr 11, 1997Jan 4, 2000Abbott LaboratoriesExtended release formulations of erythromycin derivatives
US6030642 *Jun 27, 1997Feb 29, 2000Horacek; H. JosephExtended release clonidine formulation (capsule)
US6080428 *Jan 14, 1995Jun 27, 2000Bova; David J.Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US6103261 *Jan 6, 1999Aug 15, 2000Purdue Pharma LpOpioid formulations having extended controlled release
US6129930 *Mar 6, 1997Oct 10, 2000Bova; David J.Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night
US6129933 *Jul 24, 1997Oct 10, 2000Purdue Pharma LpStabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US6143322 *Apr 8, 1997Nov 7, 2000Purdue Pharma L.P.Method of treating humans with opioid formulations having extended controlled release
US6143328 *Mar 8, 1999Nov 7, 2000Euro-Celtique, S.A.Sustained release compositions and a method of preparing pharmaceutical compositions
US6210710Apr 28, 1997Apr 3, 2001Hercules IncorporatedSustained release polymer blend for pharmaceutical applications
US6242003Apr 13, 2000Jun 5, 2001Novartis AgOrganic compounds
US6264974Jul 7, 1998Jul 24, 2001Salvagnini Italia SpaBuccal and sublingual administration of physostigmine
US6294195Sep 7, 1999Sep 25, 2001Purdue Pharma L.P.Orally administrable opioid formulations having extended duration of effect
US6306438Jul 2, 1998Oct 23, 2001Euro-Celtique, S.A.Stabilized sustained release tramadol formulations
US6372252Apr 28, 2000Apr 16, 2002Adams Laboratories, Inc.Guaifenesin sustained release formulation and tablets
US6432447May 17, 2001Aug 13, 2002Novartis AgOrganic compounds
US6551616Oct 13, 1999Apr 22, 2003Abbott LaboratoriesExtended release formulations of erythromycin derivatives
US6572885Jun 26, 2001Jun 3, 2003Euro-Celtique, S.A.Orally administrable opioid formulations having extended duration of effect
US6592901 *Oct 15, 2001Jul 15, 2003Hercules IncorporatedHighly compressible ethylcellulose for tableting
US6645527Oct 19, 2001Nov 11, 2003Euro-Celtique S.A.Stabilized sustained release tramadol formulations
US6676967Oct 31, 1997Jan 13, 2004Kos Pharmaceuticals, Inc.Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia
US6733783Oct 30, 2001May 11, 2004Euro-Celtique S.A.Controlled release hydrocodone formulations
US6746691Oct 31, 1997Jun 8, 2004Kos Pharmaceuticals, Inc.Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics
US6806294Apr 23, 2002Oct 19, 2004Euro-Celtique S.A.Opioid analgesic
US6818229Oct 31, 1997Nov 16, 2004Kos Pharmaceuticals, Inc.Intermediate release nicotinic acid compositions for treating hyperlipidemia
US6872407Nov 22, 2002Mar 29, 2005Abbott LaboratoriesExtended release formulations of erythromycin derivatives
US6905709Nov 12, 2001Jun 14, 2005Purdue Pharma, LpStabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US6955821Apr 15, 2002Oct 18, 2005Adams Laboratories, Inc.Sustained release formulations of guaifenesin and additional drug ingredients
US7122204Apr 21, 2003Oct 17, 2006Advancis Pharmaceutical CorporationAntibiotic composition with inhibitor
US7179486May 18, 2001Feb 20, 2007Nostrum Pharmaceuticals, Inc.Process for preparing sustained release tablets
US7270831Mar 20, 2003Sep 18, 2007Purdue Pharma L.P.Orally administrable opioid formulations having extended duration of effect
US7282221Nov 14, 2005Oct 16, 2007Middlebrook Pharmaceuticals, Inc.Antiviral product, use and formulation thereof
US7316821Jun 18, 2004Jan 8, 2008Purdue Pharma, L.P.Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US7476403Jun 16, 2004Jan 13, 2009Andrx Pharmaceuticals, LlcOral extended-release composition
US7514100Sep 11, 2003Apr 7, 2009Purdue Pharma L.P.Controlled release hydrocodone formulations
US7740881Jul 24, 2000Jun 22, 2010Purdue Pharma LpMethod of treating humans with opioid formulations having extended controlled release
US7838032Apr 4, 2003Nov 23, 2010Reckitt Benckiser Inc.Sustained release of guaifenesin
US7884122Nov 10, 2009Feb 8, 2011Shionogi Pharma, Inc.Extended release formulation and method of treating adrenergic dysregulation
US7943174May 17, 2011Purdue Pharma L.P.Controlled release hydrocodone formulations
US7985420Apr 4, 2003Jul 26, 2011Reckitt Benckiser Inc.Sustained release of guaifenesin combination drugs
US7985421Jun 22, 2005Jul 26, 2011Reckitt Benckiser Inc.Sustained release formulations of guaifenesin and additional drug ingredients
US7998506Aug 16, 2011Kos Life Sciences, Inc.Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US8012504Sep 6, 2011Reckitt Benckiser Inc.Sustained release of guaifenesin combination drugs
US8062672Nov 22, 2011Shionogi Inc.Antibiotic product, use and formulation thereof
US8142811Feb 17, 2009Mar 27, 2012Purdue Pharma L.P.Controlled release hydrocodone formulations
US8231898Oct 28, 2010Jul 31, 2012Purdue Pharma L.P.Controlled release hydrocodone formulations
US8236348Feb 4, 2004Aug 7, 2012Bennes, Inc.Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth
US8246996Aug 21, 2012Shionogi Inc.Antibiotic product, use and formulation thereof
US8299052Oct 30, 2012Shionogi Inc.Pharmaceutical compositions and methods for improved bacterial eradication
US8303987Nov 6, 2012Novartis AgPharmaceutical compositions comprising fluvastatin
US8303988Sep 16, 2010Nov 6, 2012Shionogi Inc.Antifungal once-a-day product, use and formulation thereof
US8313775Nov 20, 2012Shionogi Inc.Antibiotic product, use and formulation thereof
US8313776Nov 20, 2012Shionogi Inc.Antibiotic product, use and formulation thereof
US8357394Dec 8, 2006Jan 22, 2013Shionogi Inc.Compositions and methods for improved efficacy of penicillin-type antibiotics
US8361499Jan 29, 2013Purdue Pharma L.P.Controlled release hydrocodone formulations
US8425936Apr 23, 2013Shionogi Inc.Antibiotic product, use and formulation thereof
US8460710Jun 11, 2013Shionogi, Inc.Antibiotic product, use and formulation thereof
US8551520Dec 20, 2012Oct 8, 2013Purdue Pharma L.P.Controlled release hydrocodone
US8628797Dec 3, 2008Jan 14, 2014Andrx Pharmaceuticals, LlcOral extended-release composition
US8647667May 24, 2013Feb 11, 2014Purdue Pharma, L.P.Controlled release hydrocodone formulations
US8715721May 23, 2013May 6, 2014Purdue Pharma L.P.Controlled release hydrocodone
US8715727Jul 1, 2005May 6, 2014Shionogi Inc.Tablet for pulsed delivery
US8758820Aug 11, 2004Jun 24, 2014Shionogi Inc.Robust pellet
US8778924Dec 4, 2006Jul 15, 2014Shionogi Inc.Modified release amoxicillin products
US8791160Sep 14, 2012Jul 29, 2014Ferring B.V.Tranexamic acid formulations
US8809394Jul 9, 2012Aug 19, 2014Ferring B.V.Tranexamic acid formulations
US8889187Oct 14, 2011Nov 18, 2014Shionogi Inc.Once a day amoxicillin product comprising immediate and delayed release dosage forms
US8920838Apr 10, 2013Dec 30, 2014Horizon Pharma AgDelayed-release glucocorticoid treatment of rheumatoid disease
US8951555Oct 21, 2014Feb 10, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US8957113Jan 28, 2011Feb 17, 2015Ferring B.V.Tranexamic acid formulations
US8968777Feb 3, 2006Mar 3, 2015Ferring B.V.Tranexamic acid formulations with reduced adverse effects
US8975273Sep 11, 2014Mar 10, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US8980291Dec 30, 2010Mar 17, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US9023401Dec 23, 2014May 5, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US9040085Jul 11, 2014May 26, 2015Jagotec AgDelayed release tablet with defined core geometry
US9056052Feb 3, 2015Jun 16, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US9056107Mar 2, 2015Jun 16, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US9060939Sep 13, 2011Jun 23, 2015Ferring B.V.Tranexamic acid formulations
US9060940Mar 14, 2014Jun 23, 2015Purdue Pharma L.P.Controlled release hydrocodone
US9144548Oct 18, 2011Sep 29, 2015Shionogi Inc.Antibiotic product, use and formulation thereof
US9186332Dec 13, 2012Nov 17, 2015Jagotec AgDelayed release tablet with defined core geometry
US9198863Jun 2, 2015Dec 1, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US9205055Jun 2, 2015Dec 8, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US9205056Jun 2, 2015Dec 8, 2015Purdue Pharma L.P.Controlled release hydrocodone formulations
US9248095Feb 28, 2014Feb 2, 2016Shaklee CorporationNutritional supplement system
US9278074Mar 30, 2015Mar 8, 2016Purdue Pharma L.P.Controlled release hydrocodone formulations
US9289391May 7, 2015Mar 22, 2016Purdue Pharma L.P.Controlled release hydrocodone formulations
US9320717Mar 30, 2015Apr 26, 2016Purdue Pharma L.P.Controlled release hydrocodone formulations
US20020169145 *Mar 18, 2002Nov 14, 2002Rajen ShahSustained release pharmaceutical composition and method of releasing pharmaceutically active agent
US20030049318 *Apr 15, 2002Mar 13, 2003Davis Robert D.Sustained release formulations of guaifenesin and additional drug ingredients
US20030099707 *Nov 12, 2002May 29, 2003Rudnic Edward M.Antifungal product, use and formulation thereof
US20030133981 *Nov 22, 2002Jul 17, 2003Notario Gerard F.Extended release formulations of erythromycin derivatives
US20030171419 *Apr 11, 2001Sep 11, 2003Oskar KalbPharmaceutical compositions comprising fluvastatin
US20030180361 *Mar 20, 2003Sep 25, 2003Benjamin OshlackOrally administrable opioid formulations having extended duration of effect
US20030215508 *Apr 15, 2003Nov 20, 2003Davis Robert D.Sustained release of guaifenesin combination drugs
US20030235615 *Apr 21, 2003Dec 25, 2003Rudnic Edward M.Antibiotic composition with inhibitor
US20040022851 *Apr 4, 2003Feb 5, 2004Davis Robert D.Sustained release of guaifenesin combination drugs
US20040043073 *Jun 16, 2003Mar 4, 2004Chih-Ming ChenPharmaceutical compositions for drugs having pH-dependent solubility
US20040047907 *Sep 11, 2003Mar 11, 2004Benjamin OshlackControlled release hydrocodone formulations
US20040052842 *Jul 1, 2003Mar 18, 2004Rudnic Edward M.Antibiotic product, use and formulation thereof
US20040096500 *Nov 12, 2003May 20, 2004Benjamin OshlackControlled release oxycodone compositions
US20040121001 *Dec 8, 2003Jun 24, 2004Benjamin OshlackOrally adminstrable opioid formulations having extended duration of effect
US20040122065 *Nov 3, 2003Jun 24, 2004Lerner E. ItzhakPharmaceutical compositions and dosage forms for buccal and sublingual delivery of tizanidine and methods of administering tizanidine sublingually or buccally
US20040151771 *Feb 4, 2003Aug 5, 2004Gin Jerry B.Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth
US20040170680 *May 2, 2002Sep 2, 2004Benjamin OshlackOnce-a-day oxycodone formulations
US20040185098 *Mar 24, 2004Sep 23, 2004Benjamin OshlackControlled release oxycodone compositions
US20040228917 *Jun 18, 2004Nov 18, 2004Purdue Pharma LpStabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US20040247669 *Feb 4, 2004Dec 9, 2004Gin Jerry B.Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth
US20040266807 *Jun 9, 2004Dec 30, 2004Euro-Celtique, S.A.Controlled release hydrocodone formulations
US20050019401 *Jul 20, 2004Jan 27, 2005Burnside Beth A.Antibiotic product, use and formulation thereof
US20050019402 *Jul 20, 2004Jan 27, 2005Burnside Beth A.Antibiotic product, use and formulation thereof
US20050019403 *Jul 20, 2004Jan 27, 2005Burnside Beth A.Antibiotic product, use and formulation thereof
US20050037071 *Aug 11, 2004Feb 17, 2005Cao Bruce X.Robust pellet
US20050037076 *Aug 12, 2004Feb 17, 2005Burnside Beth A.Antibiotic product, use and formulation thereof
US20050048114 *Aug 20, 2004Mar 3, 2005Burnside Beth A.Antibiotic product, use and formulation thereof
US20050058706 *Apr 26, 2004Mar 17, 2005Grunenthal GmbhDelayed release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol
US20050058708 *Sep 14, 2004Mar 17, 2005Burnside Beth A.Antibiotic product, use and formulation thereof
US20050064033 *Nov 5, 2004Mar 24, 2005Notario Gerard F.Extended release formulations of erythromycin derivatives
US20050064034 *Jun 16, 2004Mar 24, 2005Andrx Pharmaceuticals, LlcOral extended-release composition
US20050118257 *May 23, 2003Jun 2, 2005Bova David J.Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US20050142187 *Dec 23, 2004Jun 30, 2005Treacy Donald J.Jr.Enhanced absorption of modified release dosage forms
US20050214368 *Apr 19, 2005Sep 29, 2005Biovail CorpControlled release formulations using intelligent polymers
US20050238714 *May 6, 2005Oct 27, 2005Rudnic Edward MAnti-fungal composition
US20050276852 *Jun 22, 2005Dec 15, 2005Adams Laboratories, Inc.Sustained release formulations of guaifenesin and additional drug ingredients
US20060003005 *Jul 1, 2005Jan 5, 2006Bruce CaoTablet for pulsed delivery
US20060039969 *Mar 28, 2005Feb 23, 2006Notario Gerard FExtended release formulations of erythromycin derivatives
US20060057210 *Aug 17, 2005Mar 16, 2006Purdue Pharma L.P.Controlled release oxycodone compositions
US20060099263 *Dec 22, 2005May 11, 2006Edgren David EAntidepressant dosage form
US20060110455 *Nov 14, 2005May 25, 2006Rudnic Edward MAntiviral product, use and formulation thereof
US20060127474 *Feb 3, 2006Jun 15, 2006Oskar KalbPharmaceutical compositions comprising fluvastatin
US20060127476 *Feb 3, 2006Jun 15, 2006Xanodyne Pharmaceuticals, Inc.Tranexamic acid formulations with reduced adverse effects
US20060159754 *Mar 21, 2006Jul 20, 2006Rajen ShahSustained release pharmaceutical composition and method of releasing pharmaceutically active agent
US20060269604 *Aug 8, 2006Nov 30, 2006Purdue Pharma L.P.Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US20070224270 *Jun 4, 2007Sep 27, 2007Bova David JNicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor
US20070225341 *Jun 4, 2007Sep 27, 2007Bova David JNicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor
US20070225342 *Jun 4, 2007Sep 27, 2007Bova David JNicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor
US20070232667 *Jun 12, 2007Oct 4, 2007Eugenio CefaliMethods for Treating Hyperlipidemia With Intermediate Release Nicotinic Acid Compositions Having Unique Biopharmaceutical Characteristics
US20070237819 *Jun 4, 2007Oct 11, 2007Bova David JNicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor
US20070237832 *Jun 8, 2007Oct 11, 2007Purdue Pharma L.P.Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US20070237833 *Jun 8, 2007Oct 11, 2007Purdue Pharma L.P.Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US20070275062 *Mar 26, 2007Nov 29, 2007Benjamin OshlackControlled release oxycodone compositions
US20070293580 *Jun 5, 2007Dec 20, 2007Malcolm HillMethods for Buccal, Lingual or Sublingual Dosing Regimens of Epinephrine for the Treatment of Allergic Emergencies
US20070293581 *Jun 5, 2007Dec 20, 2007Malcolm HillMethods for Buccal, Lingual or Sublingual Dosing Regimens of Epinephrine for the Treatment of Allergic Emergencies
US20070293582 *Jun 5, 2007Dec 20, 2007Malcolm HillEpinephrine dosing regimens comprising buccal, lingual or sublingual and injectable dosage forms
US20080020032 *Jul 20, 2007Jan 24, 2008Michael CrowleyHydrophobic abuse deterrent delivery system for hydromorphone
US20080031963 *Jun 8, 2007Feb 7, 2008Purdue Pharma L.P.Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US20080045573 *Aug 15, 2007Feb 21, 2008Bova David JMethods and Sustained Release Nicotinic Acid Compositions for Treating Hyperlipidemia
US20080050430 *May 7, 2007Feb 28, 2008Flanner Henry HPharmaceutical compositions and methods for improved bacterial eradication
US20080055036 *Aug 29, 2006Mar 6, 2008International Business Machines CorporationElectrical component tuned by conductive layer deletion
US20080075768 *Jul 20, 2007Mar 27, 2008Vaughn Jason MHydrophobic opioid abuse deterrent delivery system using opioid antagonists
US20080075770 *Jul 20, 2007Mar 27, 2008Vaughn Jason MHydrophilic abuse deterrent delivery system
US20080075771 *Jul 20, 2007Mar 27, 2008Vaughn Jason MHydrophilic opioid abuse deterrent delivery system using opioid antagonists
US20080075781 *May 17, 2007Mar 27, 2008Purdue Pharma LpControlled release oxycodone compositions
US20080132478 *Dec 4, 2006Jun 5, 2008Flanner Henry HModified release amoxicillin products
US20080181941 *Aug 17, 2007Jul 31, 2008Purdue Pharma L.P.Orally administrable opioid formulations having extended duration of effect
US20090068269 *Sep 10, 2008Mar 12, 2009Purdue Pharma L.P.Orally adminstrable opioid formulations having extended duration of effect
US20090081291 *Sep 26, 2007Mar 26, 2009Gin Jerry BSustained Release Dosage Forms For Delivery of Agents to an Oral Cavity of a User
US20090081294 *Sep 26, 2007Mar 26, 2009Gin Jerry BSustained release dosage form for lubricating an oral cavity
US20090087490 *Jun 6, 2008Apr 2, 2009Addrenex Pharmaceuticals, Inc.Extended release formulation and method of treating adrenergic dysregulation
US20090124563 *Dec 3, 2008May 14, 2009Boying LiOral extended-release composition
US20090155392 *Dec 16, 2008Jun 18, 2009Bret David NelsonMethods and Systems for Sublingual Guarana Administration
US20100034876 *Feb 11, 2010Purdue Pharma L.P.Controlled release oxycodone compositions
US20100063123 *Mar 11, 2010Addrenex Pharmaceuticals, Inc.Extended release formulation and method of treating adrenergic dysregulation
US20100092570 *Oct 15, 2009Apr 15, 2010Purdue Pharma L.P.Controlled release oxycodone compositions
US20100143533 *Feb 3, 2010Jun 10, 2010Shaklee CorporationNutritional supplement system
US20100172991 *Dec 23, 2009Jul 8, 2010Henry Joseph HoracekExtended Release Formulation and Methods of Treating Adrenergic Dysregulation
US20100209351 *Dec 8, 2009Aug 19, 2010Sackler Richard SMethod of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US20100209510 *Sep 16, 2009Aug 19, 2010Henry Joseph HoracekExtended Release Formulation and Method of Treating Adrenergic Dysregulation
US20100209514 *Aug 19, 2010Sackler Richard SMethod of treating pain by administering 24 hour oral oploid formulations exhibiting rapid rate of initial rise of plasma drug level
US20100222312 *Jan 26, 2010Sep 2, 2010Nitec Pharma AgDelayed-release glucocorticoid treatment of asthma
US20100280117 *Apr 29, 2010Nov 4, 2010Xanodyne Pharmaceuticals, Inc.Menorrhagia Instrument and Method for the Treatment of Menstrual Bleeding Disorders
US20100303919 *Dec 2, 2010Oskar KalbPharmaceutical compositions comprising fluvastatin
US20100311802 *Jul 16, 2010Dec 9, 2010Rajen ShahSustained release pharmaceutical composition and method of releasing pharmaceutically active agent
US20110052689 *Nov 5, 2010Mar 3, 2011Reckitt Benckiser Inc.Sustained release of guaifenesin
US20110065718 *Mar 17, 2011Victory Pharma, Inc.Antifungal Product, Use and Formulation Thereof
US20110230559 *Sep 22, 2011Ferring B.V.Tranexamic Acid Formulations
DE3020724A1 *May 31, 1980Jan 29, 1981Forest LaboratoriesTherapeutische praeparate mit retardwirkung
DE3246492A1 *Dec 16, 1982Jun 30, 1983Forest LaboratoriesVerfahren zur herstellung therapeutischer praeparate auf der basis von hydroxypropylmethylzellulose mit verlaengertem freisetzungsverlauf
DE3309516A1 *Mar 17, 1983Dec 1, 1983Forest LaboratoriesVerfahren zur herstellung therapeutischer praeparate mit anhaltender freisetzung auf der basis von hydroxypropylmethylzellulose mit hohem molekulargewicht
DE3834794A1 *Oct 12, 1988Apr 19, 1990F SchieleinComposition for oral administration to treat psoriasis
EP2803357A2Jun 27, 2005Nov 19, 2014The Johns-Hopkins UniversityAngiogenesis inhibitors
WO1985004100A1 *Feb 22, 1985Sep 26, 1985American Home Products CorporationSustained release pharmaceutical capsules
WO2005060941A1 *Dec 21, 2004Jul 7, 2005Sandoz AgExtended release antibiotic composition
WO2014168874A2Apr 7, 2014Oct 16, 2014The Broad Institute, Inc.Compositions and methods for personalized neoplasia vaccines
WO2016100975A1Dec 21, 2015Jun 23, 2016Massachsetts Institute Ot TechnologyMolecular biomarkers for cancer immunotherapy
Classifications
U.S. Classification424/469, 424/436, 424/430, 514/777, 424/480
International ClassificationA61K9/20
Cooperative ClassificationA61K9/2054
European ClassificationA61K9/20H6F2