WO1985003000A1

WO1985003000A1 - Controlled release liquid dosage formulations for pharmaceuticals

Info

Publication number: WO1985003000A1
Application number: PCT/US1985/000042
Authority: WO
Inventors: Ben Franklin Benton; David Lee Gardner
Original assignee: Battelle Development Corporation
Priority date: 1984-01-13
Filing date: 1985-01-09
Publication date: 1985-07-18
Also published as: JPS61500910A; ES539500A0; IT1184309B; GR850069B; ZA85239B; IT8519086A0; NZ210785A; IL74049A0; AU3835885A; EP0169236A1; ES8605975A1; CA1239347A

Abstract

A dual coated liquid dosage form sustained release pharmaceutic having substantial shelf life prior to ingestion. The dual coating is applied over controlled release dosage forms and comprises generally lipids such as fats or waxes melting at less than approximately 120oF overcoated with cellulose derivatives or prolamins. The dual coated dosage forms are dispersed in a liquid carrier such as high fructose corn syrup and display a shelf life of up to approximately at least 35 days while still retaining their controlled release profiles following ingestion.

Description

Controlled Release Liquid Dosage Formulations For Pharmaceuticals

Background of the Invention

1. Field of the Invention This invention relates to controlled release pharmaceuticals, specifically dual-coated controlled re¬ lease pharmaceuticals as a liquid dosage formulation which have substantial shelf life. More particularly, this invention relates to and discloses liquid suspens- ions of dual coated controlled release dosage forms that retain their controlled release characteristics even though dispersed in a liquid medium for a significant period of time prior to use.

2. Description of the Prior Art Controlled release forms of medication are well known in the art. Some such medications are prepared as tablets in the form of a therapeutically active core coated with various thicknesses of ingestible materials. Other time release medications take the form of an in- nocuous core coated with alternating layers of thera¬ peutically active materials and inactive ingestible ma¬ terials. More recently microcapsules or microspheres, with selected proportions of the microcapsules having coatings of differing solubilities, have been placed in conventional gelatin capsules to yield controlled release dosage forms.

Almost all controlled release pharmaceuticals to date are solids in the form of tablets, capsules, matrix materials, microcapsules, reservoir-type tablets and i- crospheres. Such forms of delivery are not always advan¬ tageous such as for administering time release drugs to very young children or to very old individuals having difficulty swallowing. An easily prepared and versatile liquid controlled release dosage formulation for delivery of a pharmaceutical, especially one which could be pre¬ packaged, would be a significant advancement.,

U.S. Patent 2,805,977 (Robinson) discloses a liquid dosage enteric preparation, however, the Robinson formulation does not teach of any formulation having any shelf life prior to administration. Robinson also does not disclose the use of the dual coating of the present in¬ vention so as to yield a liquid suspension of controlled release dosage forms that retains its controlled release characteristics even though dispersed in a liquid medium for a significant period of time prior to use.

Definitions

"Dosage form" is defined as referring to the solid carrier or housing vehicle for a therapeutically active compound exhibiting controlled release. By way of illustration, a dosage form would include any type of common prill, and would also include, for example, tab¬ lets, capsules, matrix materials, microcapsules, reser- voir type tablets, and microspheres.

"Controlled release" is understood to mean re¬ lease, preferably uniform release, of the active compound over a span of time, thus would encompass such terms as time-release, delayed release, and sustained release. "Dosage formulation" is defined as referring to the combination of dosage forms and liquid carrier in which the dosage forms are dispersed.

Summary of the Invention

It is an object of the present invention to provide a liquid controlled release dosage formulation, especially for pharmaceuticals.

It is an object of this invention to provide such liquid controlled release dosage formulation having an extended and useful shelf life, generally in excess of 35 days.

It is an object of this invention to provide a liquid suspension of dual-coated controlled release dos- age forms that retain their controlled release character¬ istics even though dispersed in a liquid medium for a significant period of time prior to use.

It is a further object of this invention to provide such dual-coated controlled release dosage forms as an easily prepared and versatile liquid controlled release dosage formulation.

The present invention relates to and discloses compositions for making liquid suspensions of controlled release dosage forms of therapeutically active compounds that retain their controlled release characteristics even though dispersed in a liquid medium for a significant period of time prior to use.

The present invention can be applied to and suc¬ cessfully used with any known solid controlled release pharmaceutical to convert it into a liquid dosage formu¬ lation having significant shelf life while still re¬ taining an acceptable controlled release profile upon ingestion. The present invention can be applied to and used with tablets, capsules, matrix materials, micro- capsules, reservoir-type tablets, microspheres and any other type of controlled release dosage form capable of being coated.

The present invention discloses use of a unique combination dual coating of fats overcoated with cel- lulose derivatives or prolamins and a liquid carrier for achieving a versatile liquid controlled release dosage formulation having substantial shelf life prior to in¬ gestion. Detailed Description of the Invention

The present invention is a controlled release liquid dosage formulation for pharmaceuticals. The pres¬ ent invention discloses use of a unique combination of dual coatings of controlled release type dosage forms in combination with a suitable liquid carrier. Suitable con¬ trolled release type dosage forms useful in the practice of the present invention include tablets, capsules, con- trolled-release matrix beads, microcapsules, reservoir- type tablets, and microspheres, all by way of example and not limitation.

In this invention, suitable controlled release type dosage forms, preferably microspheres, are coated with at least two different materials. The first coating is with a hydrophobic, digestible or degradable material preferably having a melting point of approximately 120°F or lower such that the coating would be almost liquid or rendered permeable following ingestion. The first coat¬ ing over said dosage forms can be a lipid including a fat, a fatty acid, fatty alcohol, wax, ester or mixtures thereof, having a melting point of less than 120°F. The first coating preferably is one or more fats, i.e., glycerides composed of fatty acids of from 3 to 22 carbons, with said glycerides or blends of glycerides having a melting point of 120°F or less. It is to be understood by those skilled in the art that most fats or glycerides include minor percentages of sterols, hydrocarbons, to- copherols and other nonglyceride constituents. The fats or glycerides can include mono-, di-, or triglycerides or glyceryl esters, phosphatides, phosphoglycerides, or mix¬ tures thereof. The first coating is, preferably, a hard butter such as cocoa butter, or partially hydrogenated cottonseed and/or soybean vegetable oil such as Kaomel* (Durkee) which has a Wileymelting point of 97-101°F. Also useful for the first coatings are: animal fats, tallow; shortening; lard including modified lard; vegetable oils including partially hydrogenated vegetable oils; beeswax; lecithin; butterfat; oleic acid; elaidic acid; margarine; or blends of any of the foregoing.

It is to be understood that melting point is an approximate term when applied to fats, waxes, fatty acids and esters since these materials melt over a range of temperature.

Melt point determination techniques have been established by the Fat Analysis Committee of the American Oil Chemists' Society such as AOCS Method Cc 2-38 Wiley Melting Point and AOCS Method Cc 3-25.

The first coating can be a fat, fatty acid, fatty alcohol, wax, ester, or mixture thereof having a melting point of less than approximately 120°F or capable of being rendered permeable following ingestion.

Substances useful as the first coating include mono-, di-, and triglycerides composed of fatty acids of from 3 to 32 carbons; wax esters composed of fatty acids of from 3 to 36 carbons and composed of alcohols of from 8 to 46 carbons; fatty alcohols of from 8 to 54 carbons; hydrocarbons of from 18 to 54 carbons; olefins of from 18 to 54 carbons, and free fatty acids of 8 to 36 carbons, all additionally having a melting point below approximately 120°F or capable of being rendered permeable following ingestion.

The waxes making up the first coating can in¬ clude, by way of illustration and not limitation; wax hydrocarbons - such as n - alkanes and branched alkanes, olefins, cyclic alkanes and isoprenoid hydrocarbons; ketones such as monoketones, 8- diketones, wax alcohols - such as secondary alcohols and alkane diols, wax acids - such as alkanoic and alkenoic acids, - or ω- hydroxy acids, and wax esters - such as primary alcohol esters, secondary alcohol esters, diester waxes, alkane diol di- esters, diesters of hydroxy acids, triesters, trigly- cerides, triesters of alkane -1,2 -diol, ω- hydroxy acid and fatty acid; esters of hydroxy malonic acid,,fatty acid and alcohol; triesters of hydroxy acids, fatty acid and fatty alcohol; triesters of fatty acid, hydroxy acid and diol.

Over the first coating, an overcoat or second coating is provided which is: 1) amenable to being render¬ ed permeable in early portions of the gastrointestinal tract, preferably within approximately the first hour of entering the gastrointestinal tract; and 2) able to pre¬ vent agglomeration or clumping of the coated microcap¬ sules or microspheres.

It is this combination of coatings (first and second overcoating of the microspheres) which permit the dosage form to be successfully placed in a liquid carrier vehicle for at least 35 days prior to ingestion. This combination of coatings helps maintain dispersibility of the dosage forms while physically retaining the thera- peutically active compound or active drug within the dosage form prior to actual ingestion of the liquid dosage formulation.

Compounds useful for the second coating or overcoating include: the prolamins, such as zein, glia- din, or hordein; also carotin; also starch and its deriva¬ tives; also cellulose derivatives, such as the dibasic acid monoester derivatives of cellulose including cellu¬ lose acetate phthalate and cellulose acetate succinate, also cellulose derivatives such as carboxymethyl cellu- lose acetate, carboxymethyl ethyl cellulose, carboxy¬ methyl hydroxypropyl cellulose acetate, carboxymethyl cellulose stearic acid, also cellulose ethers such as ethyl cellulose. Compatible blends of any of the fore¬ going can also be used. The second coating should be selected so as to be generally nonsoluble in the carrier liquid, however, rendered permeable in the gastrointestinal tract. Vari¬ ous means of rendering the second coating permeable can be employed. For example, the second coating can be pH sensitive, meaning soluble in only a limited range of pH i.e., alkaline soluble in the GI tract; or the second coating can be broken down by enzymes such as Upases, proteases, or a alases, i.e., the second coating, can be a protein which is broken down by any of various proteases in the gastrointestinal tract; or the second coating can be a starch broken down by enzymes such as amalase within the GI tract. The preferred materials for the second coating or overcoating are zein or cellulose acetate phthalate.

Any common plasticizer such as diethyl ptha- late, tributyl citrate, tributyrin; triacetin, castor oil, partially or fully acetylated monoglycerides or butyl phthalyl butyl glycolate can be employed in either or both coatings to impart desired or what is deemed suitable flexibility, workability or resiliency to the coating. The plasticizer can also be used to modify the permeability of the respective coating.

The dual coated microspheres or dual coated controlled release dosage form can be dispersed in the carrier or delivery liquid medium. While water may be used as the carrier liquid it is preferred to add thickeners to assure uniform dispersion. More preferred, since many pharmaceutical drugs have a degree of water solubility, are liquid carriers which diminish the amount of available water such as aqueous solutions of colloidal carbohy¬ drates or sugar syrups. Many suitable carrier liquids can be employed, such as, by way of illustration and not limitation, high fructose corn syrup, honey, sugar syrup, an aqueous solution of carboxymethyl cellulose, glycerin, gum arabic, agar, or gelatin. Miscible combinations of the foregoing are also possible. In the preferred embodi- ment, the delivery medium is chosen so as to reduce the proportion of water available to leach the active drug from the dual coated dosage form, but also to-be palat¬ able to the recipient of the liquid dosage formulation. Slightly acid carrier liquids are preferred since they also tend to retard microbial growth. High fructose corn syrup was found to be a particularly suitable delivery medium as such syrup has only approximately 30% water and is naturally acidic. In general the liquid carrier is best selected so as to be a poor solvent of the particular pharmaceutic.

Sugar solutions and sugar syrups are useful as the carrier liquid from the aspect of limiting the avail- able water but also as a preservative. Though any of the foregoing liquids can be used as the carrier liquid inwhich the dual coated dosage forms are dispersed, it is advantageous where possible to select a carrier liquid such that the active drug held in the dual coated dosage form is not soluble or only minimally solu- ble in the carrier liquid.

In the preferred embodiment, the present in¬ vention provides an improved delivery vehicle for con¬ trolled release dosage forms, which dosage forms are understood to include controlled-release matrix beads, microspheres, microcapsules, or reservoir type capsules or devices, by enabling preparing of liquid formulations of such dosage forms having a substantial shelf life. Microspheres, microcapsules, and matrix beads are pre¬ ferred dosage forms, especially in the size range of 15 microns to 7000 microns.

The microspheres and controlled release dosage forms useful for the purposes of being dual coated accord¬ ing to the invention can be prepared by any of several known microencapsulation processes or microsphere or ma- trix bead production processes including pan coating, prilling, granulation fluidization processes, pressing through fine mesh screens and other processes.

Though particularly suitable for controlled release microspheres packageable and administrable in a liquid formulation intended for young children or the elderly, this invention can also be practiced with any of the earlier-mentioned controlled release type dosage forms. Also larger, relatively speaking, controlled- release tablets, capsules, devices, spheres or matrix beads coated according to the present invention can pro¬ vide dosage forms suitable for preparation in a liquid formulation, for example, in veterinary applications, where micro sizes become relative to the size of the recipient. The liquid suspension of dual coated controlled release dosage forms according to this invention can be prepared in advance in many cases as early as 35 days or sooner before the intended day of administration of the liquid formulation. Upon ingestion of the liquid dosage formulation, the controlled release characteristics of the dual coated microspheres are expressed with active drug release commencing in the upper gastrointestinal tract and active drug release continuing at a uniform rate thereafter for at least 8-12 or 24 hours. The controlled release liquid dosage formu¬ lations of the present invention are particularly suit¬ able for such drugs as theophylline, dimethylxanthine, antihistamines, cold formulations, analgesics, amino acid supplements, geriatric drugs such as sleeping aids and blood pressure regulators, antidepressants such as lith¬ ium chloride, also potassium salts, and alkaloids such as caffeine and codeine.

The following example serves to illustrate the invention, however, the invention is not to be construed as limited thereto. EXAMPLE

Theophylline was selected to illustrate the dual coated dosage form and liquid dosage formulation of the present invention. Theophylline was selected to illustrate the scope of the invention since a suitable liquid dosage formulation, especially one in which the¬ ophylline is the therapeutically active compound, must satisfy a particularly rigid controlled-release profile. Theophylline is a representative alkaloid drug. lt is isomeric with dimethylxanthine and the common alka¬ loid, caffeine, differs from theophylline by one less methyl group. Theophylline, typical of alkaloids, is bitter.

Theophylline is used as an antiasthmatic but it has an unpleasant taste and requires careful dose mea¬ surement and administration to maintain therapeutic serum concentrations. Especially with young children, the now required every 4-6 hour round-the-clock dosing levels of theophylline are difficult to administer and maintain. ^children often dislike the taste.

It is held by some in the field that theophyl¬ line is a tissue irritant and thus is preferred to be administered in an enteric release form.

Thus, the preferred controlled release liquid dosage formulation containing theophylline according to this invention should satisfy the rigid criteria of:

1) withhold release to the carrier liquid when stored as a liquid formulation so as to have significant shelf life, preferably at least 35 days; 2) begin release of the active drug 1 hour after entering the gastrointestinal tract;

3) continue uniform sustained release of the active drug for at least 8 to 24 hours.

It has been found that the liquid dosage formu- lation of the present invention is particularly advan- tageous for the administering of theophylline. A liquid dosage formulation sustaining theophylline release up to 12 or 24 hours according to this invention would_.be parti¬ cularly beneficial to asthmatic children, would be easy to administer because of the liquid carrier and its masking of the unpleasant taste, and would require less frequent administration.

With a stable shelf life in excess of 35 days, the premixed liquid dosage formulation would be practical for dispensing by pharmacies.

Examples of five commercially available con¬ trolled release type dosage forms are illustrated below. The active drug is theophylline in these preparations.

1. Aerolate*, 1, 2 and 4 grain capsules (Flem- ming and Company, St. Louis, Missouri) .

2. Theo-Dur* 100, 200 and 300 mg scored tablets (Key Pharmaceuticals, Inc., Miami, Florida)

3. Theo-Dur Sprinkle®, 50, 75, 125 and 200 mg strengths (Key Pharmaceuticals, Inc., Miami, Florida). 4. Slo-Phylline Gyrocaps*, 60, 125 and 250 mg capsules (Dooner Laboratories, Inc., Haverhill, Massachu¬ setts) .

5. Sustaire* tablet (Roerig, Division of Pfi¬ zer, Inc., New York, New York). Based upon the release profile of these sus¬ tained release type products, the Theo-Dur* scored tab¬ lets and Slo-Phylline Gyrocaps* when placed into apple¬ sauce exemplify the typical "liquid dosage formulation" available today. Tested for release of theophylline via serum levels it was found that after 1 hour, the Theo-dur^β scored tablets had released 10% of their theophylline and the Slo-Phylline Gyrocaps* had released 80% of their theo¬ phylline. The typical controlled release dosage form available today does not have any significant shelf life in an aqueous based carrier fluid since appreciable re- lease proceeds from the initial time of dispersion in the carrier liquid.

Source of Typical Controlled Release Test Dosage Forms Typical sustained release dosage forms in the 5 form of spherical beads or microspheres are readily ob¬ tained from commercial sources. In this case, the micro¬ spheres were obtained from Central Pharmaceuticals, Inc. ,

- 110-128 E. Third Street, Seymour, Indiana. The following analysis was provided:

10 Product 48.15% Theophylline Anhydrous Sustained Release Beads

Analyzed for Label Claim Found % of Claim

Theophylline Anhydrous 48.15% 49.4% 102.6%

Release Rate: 5 Method - USP Dissolution Apparatus 2 operated at

50 RPM

Released in:

Limits

1 hour 10. .1% 5, .0-20 .0% 0 2 hours 27, .9% 20, .0-40 .0%

4 hours 61. .0% 50, .0-85 .0%

6 hours 79. .3% NLT 65. 0%

8 hours 89, .1% NLT 85. 0%

Process for Coating Controlled Release Test Dosage Forms 5 in a fluidized bed process the above mentioned controlled release test dosage forms in the form of spher¬ ical beads containing theophylline were sprayed with a solvent solution of Kaomel* (Durkee) which is a partially hydrogenated cottonseed and soybean vegetable oil. This 0 oil has a Wily melting point of 97-101°F and solid fat index (SFI) values as follows: 50°F = 69% min; 70°F = 54% min; 80°F = 53% min; 92°F = 22% min; 100°F = 5% max. The Kaomel•coated beads were then coated either with zein or cellulose acetate phthalate (CAP) . A plas¬ ticizer was included to enhance the coating properties of the zein and CAP. With zein, the plasticizer used was 05 Myvacet* (Eastman Kodak) a distilled acetylated mono- glyceride. With cellulose acetate pthalate a butyl ptha- lyl-butyl glycolate liquid sold as Sanitizer* (Pfizer) was used as a plasticizer.

The following types of coated dosage forms were 10 prepared for testing (all percents given are by weight) .

Table 2

# 1 - uncoated dosage form

# 2 - dosage form coated with 17.7% Kaomel # 3 - dosage form coated with 17.7% Kaomel followed by 4.33% cellulose acetate phthalate

# 4 - dosage form coated with 17.7% Kaomel followed by

4.33% cellulose acetate phthalate containing 1.7% plasticizer # 5 - dosage form coated with 17.7% Kaomel followed by 4.0% Zein containing 0.9% plasticizer

# 6 - dosage form coated with 17.7% Kaomel followed by 2.2%

Zein containing 0.9% plasticizer

# 7 - dosage form coated with 4.76% Kaomel followed by 2.37% cellulose acetate phthalate containing 1.0% plasticizer

# 8 - dosage form coated with 4.78% cellulose acetate phthalate containing 1.92% plasticizer

# 9 - dosage form coated with 2.41% cellulose acetate phthalate containing 0.97% plasticizer #10 - dosage form coated with 4.76% Kaomel

(All percentages are on the basis of total weight of coated dosage form) Four release tests (A thru D below) were de¬ signed to assess release characteristics of the various coated dosage forms.

Assessment of Release to Liquid Carrier (A) dosage form placed in a high fructose corn syrup solution and theophylline release determined after 7 or 14 days.

(B) dosage form placed in a phosphate buffer (pH 6.0) and release of theophylline determined after 1, 3 and 7 days.

(C) dosage form placed in a phosphate buffer (pH 4.5) and release of theophylline determined after 1, 3 and 7 days.

Assessment of Release Profile in Gastrointestinal Tract (D) dosage form placed in simulated gastric fluid (pH ~1.2) for 1 hour, followed by placement in simulated intestinal fluid (pH~7.5) over the next 7 hours. Theophylline release was determined at 1, 2, 3, 4, 5, 6 and 8 hours.

In conducting the (B) and (C) in vitro release studies, approximately 100 milligrams of selected dosage forms were placed in a test tube containing 10 ml of the phosphate buffer (either pH 6.0 or pH 4.5) test solution. These studies were conducted at ambient temperature with the test tube contents mixed via a Lab Quake test tube rotator. At predetermined times, the test solution was drawn off. Fresh test solution was then added back to the test tube. The procedure of drawing off the test solution was performed on days 1, 3 and 7. The test solutions removed on days 1, 3 and 7 were filtered and refrigerated until assayed for theophylline.

In conducting the (A) invitro release study, the principal difference was that high fructose corn syrup (HFCS, Corn Sweet* 42, Archer Daniels Midland Co.) was substituted as the test solution for the phosphate buffer. Other aspects of this _in vitro release study were similar to those described for (B) and (C) .

The (D) in vitro release study was similar to the (B) and (C) _in vitro release studies with the exception of duration, temperature and test solution. All (D) jln vitro release studies were conducted at 37 C by placing the test tubes on the Lab Quake rotator in a thermostatistic- ally-controlled oven. The test solution for this in vitro release study was a simulated gastric fluid during the first hour followed by a simulated intestinal fluid.

The simulated gastric fluid was prepared as follows:

2.0 g of sodium chloride and 3.2 g of pepsin was dissolved in 7.0 ml of hydrochloric acid and sufficient water to make a 1000 ml solution. This test solution has a pH of about 1.2.

The simulated intestinal fluid was prepared as follows: 6.8 g of monobasic potassium phosphate was dis¬ solved in 250 ml of water. With stirring, 190 ml of 0.2 N sodium hydroxide was added along with 400 ml of water. 10 g of pancreatin was then added with stirring. The pH of the resulting solution was adjusted to apH of 7.5 + 0.1 by the addition of 0.2 N sodium hydroxide, then the so¬ lution was diluted with water to 1000 ml.

Theophylline release in the simulated gastric fluid test solution followed by simulated intestinal fluid test solution was determined at the end of 1, 2, 3, 4, 5, 6 and 8 hours.

In all the iji vitro release studies A through D, theophylline was assayed by a reverse phase high pressure liquid chromatography (HPLC) technique as set forth by L.C. Franconi et. al., "Determination of Theophylline in Plasma Ultra iltrate by Reversed Phase High Pressure Liquid Chro- matography," Anal. Chem., 48: 372, 1976. The results of the (A) i_n vitro release study

(Table 3} show that when the dosage form is placed in high fructose corn syrup, HFCS, an acidic environment, several dosage forms show extremely low levels of theophylline release. In particular, type #4 dosage form released only 0.2 percent of the available theophylline over a 14-day period. The uncoated dosage form under these same condi¬ tions and duration released 14.8% of the available the¬ ophylline. Another four types #'s 5, 7, 8 and 10 exhibited less than 1 percent release after 7 days. The reduced amount of theophylline released is due primarily to the coatings placed over the controlled release dosage forms. The low percentage of water in the HFCS, i.e., 29 percent, tends to further minimize the amount of theophylline which 5 is released. Theophylline solubility in water =8.3 mg/ml. The results of the (B) and (C) in vitro release studies (Tables 4 and 5) verify the importance of the liquid carrier pH in which the dosage form will be eventually formulated. For instance, in Table 4, the lowest per- _Qcentage of theophylline release from the #4 type dosage form was 47.1%. However, in Table 5, when this same type #4 dosage form was placed in an acidic environment (pH 4.5) , the theophylline release had dropped to 1.8%. Addi¬ tionally, the dosage form overcoated with Kaomel®-CAP produced the least amount of theophylline release. The importance of these two coatings, i.e., Kaomel* and CAP, is clearly established if compared with dosage form types #8 and #9 (See Table 5) . Table 3 Results of In Vitro Release Study (A)

High Fructose Corn Syr up Solu ition l [HFCS)

05 Day (mg

Theophylline

Released) Total % of Available

Prill Type Weight, Available 7 th 14th Theophylline Theophylline

Coating* (see Table 2) mg Theophylline, mg day day Released, mg Released

10 u # 1 102.3 50.5 6.85 6.85 13.6 k/c # 4 105.5 39.8 0.04 0.04 0.08 0.2 u # 1 102.5 50.6 2.89 4.58 7.47 14.8 u # 1 499.4 240.5 15.21 15.21 6.2

15 k #10 525.0 240.2 1.84 1.84 0.7 c # 8 535.5 239.8 0.30 0.30 0.1 k/z # 5 630.4 224.6 1.63 1.63 0.7 k/c # 7 540.2 238.0 1.04 1.04 0.4

20 *u = uncoated k = Kaomel* c = cellulose acetate pthalate l k/c = Kaomel* overcoated with cellulose acetate pthalate z = zein

25 k/z = Kaomel® overcoated with zein

Table 4 Results of In Vitro Release Study (B) pH 6.0 Studies

05 Day (mg Theophylline Total % of Available

Type of Prill Weight, Released) Theophylline Theophylline

Coating (Refer to Table 2) mg 1 3 7 Released, mg Released

10 u #1 102.5 27.8 1,2.6 0.7 41.1 81.1 u #1 102.2 20.6 '^' 5.9 0.3 26.7 52.9 u #1 103.8 26.9 8.0 0.6 35.5 69.1 k #2 103.5 0.7 4.5 11.6 16.8 39.8 k #2 103.7 1.6 3.6 8.9 , 14.1 33.4

15 k/c #3* 102.9 19.0 1.9 0.0 20.9 41.1 k/c #3 103.9 4.7 6.9 25.2 36.7 91.8 k/c #4* 103.3 18.4 6.9 0.5 25.8 61.3 k/c #4 103.3 0.3 3.4 14.6 18.3 47.1 k/z #5 106.6 0.1 0.6 10.3 11.0 26.6

20 k/c #7 106.1 10.7 24.8 4.0 39.6 82.2 c #8 105.2 26.8 9.9 0.5 37.2 ¹ 76.6 c #9 106.1 25.5 9.8 0.8 36.0 71.2

* 10 ml liters of Triton* x-100 surfactant added to test solution. (Because of high

25 levels of release on day 1, addition of surfactant to the carrier liquid is contra-indicated and therefore not preferred in this invention.)

Table 5

Results of In Vitro Release Study (C) pH 4.5 Studies

05 Day (mg

Theophylline Total % of Available

Type of Prill Weight, Released) Theophylline Theophylline

Coa ting (Refer to Table 2) mg 1 3 7 Released, mg Released

10 k/c #3 104.9 3.4 7.8 19.4 30.7 75.8 1 k/c #4 105.1 0.1 0.2 0.5 0.8 1.8 k/z #5 104.8 0.1 0.8 9.3 10.2 25.0 1 k/z #6 105.4 0.1 0.2 1.0 1.3 3.1 k/c #7 105.1 1.0 10.5 16.8 28.3 59.2

15 c #8 107.9 1.1 3.5 5.8 10.4 21.4 c #9 105.5 1.1 5.5 13.6 20.2 40.2

#3 - pr ills did not possess i good morphology 1

#7 - both the Kaomel*, CAP and plasticizer level were reduced as compared

20 to #4 -

Since only a very small percentage of theo¬ phylline release had occurred over a 7 day period with the type #4 dosage form in an acidic environment, this same type dosage form was followed for 35 days in a pH 4.5 phosphate buffer solution. In this study, the total theophylline released over a 35 day period was determined to be 5.85 percent (See Table 6) . This figure is believed to be upwardly biased since the test solution was changed every 7 days with fresh test solution. This changing of solution increased the concentration gradient between the coated dosage forms and the liquid environment. Absent the solution changing, the actual amount of theophylline released would approximate 1.3 percent. This is based upon the fact that the actual amount of theophylline released at the end of each 7 day period approximated 0.4 - 0.5 mg. The total amount of theophylline originally available for release from the type #4 prill was 39.3 milligrams, i.e., 0.5 * 39.3 = 1.3 percent.

This latter study represents a situation in which the medium is essentially 100% water. Thus, even under these severe test conditions, very little theophyl¬ line was released. Thus, the importance of these coat¬ ings, as they relate to the pH of the liquid environment, is demonstrated.

Table 6

Release of Theophylline From Dosage Form

Over a 35-Day Period

(pH 4.5 phosphate buffer solution)

05

Total

Type of Dosage Form Days (mg Theophylline Released) Theophylline Coating (Refer to Table 2) Weight 7 14 21 28 35 Released, mg %

10 k/c #4 104 .2 0 .4 0 .4 0.5 0.5 0 .5 2.3 5.9

It can be seen from Table 7 that the dosage forms overcoated with cellulose acetate phthalate alone do not yield acceptable controlled release characteristics as such dosage forms release a high burst of theophylline in the second hour of the test. The relea^'se rates of the CAP alone coated dosage forms exceed even that of the uncoated dosage forms. Kaomel* alone as a coating was found to be unworkable for several reasons including problems of clumping or aggregation. Uniform dosage levels of Kaomel* alone coated dosage forms were difficult to measure and the clumping tended to reduce available surface area thus giving rise to questions as to reproducibility of release profiles. The present invention unexpectedly requires dual coated dosage forms to provide a liquid suspension of controlled release formulations having substantial shelf life that retains its controlled release characteristics.

Table 7 Results of In Vitro (D) Release Study

(Synthetic Gastric Then Synthetic Intestinal Solu tion)

05 % of

Dosage Form Tptal Availabl

Type Weight, Hours (mg Theophylline Released) ' Theophylline Theophylli

Coating (see Table 2) mg 1 2 3 4 5 6 8 Released, mg Release

10 u #1 101.0 9.6 5.1 4.7 4.0 4.0 3.2 3.4 34.1 68.

(17.7%) k #2 102.9 0.1 0.2 0.8 0.9 1.2 2.1 4.3 9.5 22. k/c #3 104.8 0.1 0.7 1.3 1.4 1.6 2.2 5.5 12.9 31. k/c #4 106.3 0.0 0.1 0.5 0.8 1.0 1.5 3.3 7.3 18. k/z #5 105.5 0.1 0.7 4.7 12.9 8.5 3.1 0.2 30.3 74.

15 k/z #6 106.3 0.0 0.3 1.5 2.2 7.1 8.0 9.5 28.7 68.

(4.8%) k #10 105.4 0.4 3.2 5.0 6.3 8.2 7.2 12.3 42.7 86. k/c #7 106.2 0.1 1.8 3.1 4.5 5.7 7.3 18.5 41.1 85. c #8 107.0 0.2 23.8 6.1 0.2 0.0 0.0 0.0 30.4 61. c #9 107.0 0.3 34.3 4.8 0.3 0.0 0.0 0.0 39.8 77.

20

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Claims

1. A liquid formulation of dual coated con¬ trolled release dosage forms comprising: a) a controlled release dosage form containing a therapeutically active compound; b) a first coating over said dosage form which comprises one or more hydrophobic, digestible or de¬ gradable substances having a melting point of 120°F or less such that said first coating is a liquid or is rendered permeable following ingestion; c) a second coating over said first coating which is capable of preventing agglomeration of the dual coated dosage forms and amenable to being ren¬ dered permeable after entering the gastrointestinal tract; and d) a liquid carrier for dispersing therein of said controlled release dosage forms having a first coating and a second coating.

2. The claim according to Claim 1 wherein said first coating comprises a lipid.

3. The claim according to Claim 1 wherein said first coating comprises a fat, wax, fatty acid, fatty alcohol, or ester having a melting point of 120°F or less.

4. The claim according to Claim 3 wherein said wax comprises one or more wax hydrocarbons, wax alcohols, wax acids, wax esters or mixture thereof.

5. The claim according to Claim 1 wherein said first coating comprises one or more glycerides composed of fatty acids of from 3 to 32 carbons, said glycerides or blends of glycerides having a melting point of approxi¬ mately 120op _or less.

6. The claim according to Claim 5 wherein sai first coating comprises a glyceride selected from the grou consisting of hard butter, cocoa butter, butterfat, vege¬ table fat, vegetable oil, tallow, lard, shortening, oleic acid, elaidic acid, margarine, and mixtures thereof.

7. A liquid formulation of controlled release dosage forms according to Claim 1 wherein said second coating over said first coating comprises one or more prolamins, cellulose derivatives, cellulose ethers, or starches.

8. The claim according to Claim 1 wherein said second coating over said first coating comprises cellulose acetate phthalate, cellulose acetate succinate, carboxyl methyl ethyl cellulose acetate, ethyl cellulose, carboxy methyl cellulose, carboxymethyl hydroxy propyl cellulose acetate, carboxymethyl cellulose stearic acid, zein, gli- adin, hordein, carotin, or starch.

9. The claim according to Claim 1 wherein said first coating and/or said second coating includes in addi- tion a plasticizer.

10. The claim according to Claim 9 wherein said plasticizer is selected from the group consisting of di- ethyl phthalate, tributyl citrate, tributyrin, triacetin, castor oil, partially or fully acetylated monoglycerides, or butyl phthalyl butyl glycolate.

11. The claim according to Claim 1 wherein said second coating is rendered permeable in the gastrointest¬ inal tract by an enzyme.

12. The claim according to Claim 11 wherein said enzyme is an enzyme selected from the group consisting of proteases, a alases and Upases.

13. The claim according to Claim 1 wherein said 5liquid carrier is of a pH so as not to solubilize the second coating and said second coating is soluble in a limited range of pH.

14. The claim according to Claim 13 wherein said second coating is rendered permeable in the gastrointest- oinal tract due to the pH of the gastrum or intestines which pH is dissimilar to the pH of the liquid carrier.

15. The claim according to Claim 1 wherein said liquid carrier is a liquid selected from the group con¬ sisting of aqueous solutions of colloidal carbohydrates, 5sugar, agar, gum arabic, or carboxymethyl cellulose.

16. The claim according to Claim 1 wherein said liquid carrier is a liquid selected from the group con¬ sisting of water with thickeners, high fructose corn syrup, honey, sugar syrup, glycerin, or gelatin solution.

o 17. The claim according to Claim 1 wherein said dual coating, on the basis of the total weight of the dual coated dosage form, consists of: a first coating of not more than 25% by weight of partially hydrogenated vegetable oil; 5 a second coating of not more than 10% by weight cellulose acetate phthalate.

18. The claim according to Claim 17 wherein said first coating has a melting point of approximately 101°F or less.

19. The claim according to Claim 1 wherein said dual coating, on the basis of the total weight of the dual coated dosage forms, consist of a first coating of not more than 25% by weight of partially hydrogenated vegetable oil a second coating of not more than 10% by weight of zein and plasticizer.

20. The claim according to Claim 1 wherein said therapeutically active compound is selected from the group consisting of alkaloids, theophylline, dimethylxanthine, antihistamine, analgesics amino acid supplements, lithium chloride, potassium salts, caffeine, codeine, geriatric drugs, cold or flu remedies, sleeping inducing drugs, blood pressure regulators, and antidepressants.

21. The claim according to Claim 1 wherein said dosage forms have a size from 15 microns to 7000 microns.

22. The claim according to Claim 21 wherein said dosage forms are selected from the group consisting of microspheres, microcapsules, matrix beads, tablets, cap¬ sules and reservoir-type tablets.

23. A process for preparing a liquid formulation of dual coated controlled release dosage forms comprising the steps of: a) coating controlled release dosage forms having a therapeutically active compound with a hy- drophic digestible or degradable substance having a melting point of 120°F or less so as to form a first coating; b) overcoating said first coating with a second coating which is amenable to being rendered permeable within the first hour of entering the gastrointestin¬ al tract and capable of preventing agglomeration of the dual coated dosage forms; and c) dispersing the dual coated dosage forms in a liquid carrier.

24. The claim according to Claim 23 wherein said dual coated dosage forms are dispersed in said liquid carrier a substantial time prior to ingestion.

25. The claim according to Claim 23 wherein said dual coated dosage forms are dispersed in said liquid carrier up to at least 35 days prior to ingestion.

26. The claim according to Claim 23 wherein said dual coated dosage forms are dispersed in a liquid carrier selected from the group consisting of water, high fructose corn syrup, honey, sugar syrup, an aqueous solution of carboxy methyl cellulose, glycerin, gum arabic, agar, gelatin, and miscible mixtures thereof.

27. The claim according to Claim 23 wherein said dosage forms are encapsulated with a first coating com¬ prising a lipid.

28. The claim according to Claim 23 wherein said dosage forms are encapsulated with a first coating of one or more mono-, di-, or triglycerides, glyceryl esters, phosphatides, or mixtures thereof having a melting point of approximately 120°F or less.

29. The claim according to Claim 23 wherein said dosage forms are encapsulated with a first coating of one or more glycerides composed of fatty acids of 3 to 32 carbons, said glycerides or blend of glycerides having a melting point of approximately 120°F or less.

30. The claim according to Claim 29 wherein said dosage forms are encapsulated with a first coating of a fatty acid selected from the group consisting of hard butter, cocoa butter, butterfat, vegetable fat, vegetable oil, tallow, lard, shortening, oleic acid, elaidic acid, margarine, and mixtures thereof.

31. The process according to Claim 24 wherein said first coating is overcoated with a second coating comprised of a substance selected from the group consisting of cellulose acetate pthalate, cellulose acetate succin- ate, carboxyl methyl ethyl cellulose acetate, ethyl cel¬ lulose, carboxy methyl cellulose, carboxymethyl hydroxy propyl cellulose acetate, carboxymethyl cellulose stearic acid, zein, gliadin, hordein, carotin, and starch.

32. The claim according to Claim 24 wherein said second coating is soluble in a limited range of pH and said liquid carrier is of a pH so as not to solubilize the second coating.

33. The claim according to Claim 32 wherein following ingestion of said pharmaceutic said second coat¬ ing is rendered permeable in the gastrointestinal tract due to the pH of the gastrum or intestines which pH is dis¬ similar to the pH of the liquid carrier.

34. The claim according to Claim 24 wherein following ingestion of said pharmaceutic said second coat¬ ing is rendered permeable in the gastrointestinal tract by an enzyme.

35. The claim according to Claim 24 wherein following ingestion of said dual coated liquid formulation of dual coated controlled release dosage forms, a thera¬ peutically active compound is released over a span of from 8 to 24 hours from said formulation.

36. The claim according to Claim 35 wherein said therapeutically active compound is selected from the group consisting of theophylline, dimethylxanthine, antihista- mine, analgesics, amino acid supplements, lithium chlor¬ ide, potassium salts, caffeine, geriatric drugs, sleep- inducing drugs, blood pressure regulators, or antide- pressants.