WO1983002056A1

WO1983002056A1 - Expandable lattice of polyvinyl alcohol and polyethylene glycol

Info

Publication number: WO1983002056A1
Application number: PCT/US1982/001771
Authority: WO
Inventors: Inc. Key Pharmaceuticals; Alec Keith
Original assignee: Key Pharma
Priority date: 1981-12-18
Filing date: 1982-12-20
Publication date: 1983-06-23
Also published as: EP0096074A1; JPS58502097A; EP0096074A4

Abstract

An expandable lattice structure is a film of polyvinyl alcohol and polyethylene glycol having sufficient thickness to retain its structural integrity upon the application of an osmotic pressure and sufficient thinness whereby said expandable lattice structure is capable of sufficient expansion of its lattice structure under the influence of osmotic pressure whereby drug molecules are permitted to pass therethrough.

Description

EXPANDABLE LATTICE OF POLYVINYL ALCOHOL AND POLYETHYLENE GLYCOL

Summary of the Invention A dosage form is provided for oral administration of drugs, for example, quinidine or propranolol, to a patient which comprises a core containing the drug and a coating of an expandable lattice, said expandable lat¬ tice permitting the passage of water therethrough resul¬ ting in dissolution of the drug and which under condi¬ tions of osmotic pressure is expanded to a state whereby molecules of the drug are permitted to pass there¬ through, said expandable lattice retaining its struc¬ tural integrity, said dosage form when contacted with the aqueous medium of the gastro-intestinal tract taking up water in said core through passage of water through said expandable lattice, whereby an osmotic pressure is built up causing said expandable lattice to expand re¬ sponsive to said osmotic pressure, said drug being permitted to escape through the resultant expanded lattice structure of said expandable lattice.

In a preferred embodiment, the expandable lattice contains polyvinyl alcohol, preferably having a mole¬ cular weight of at least 75,000. In a particularly preferred embodiment, the expandable lattice contains polyvinyl alcohol having a molecular weight of from about 75,000 to about 150,000. In a further embodiment, the expandable lattice also contains polyethyleneglycol having a molecular weight of from about 400 to about 4000. Detailed Description of the Invention In accordance with the present invention, tablets covered with an expandable lattice are provided that take advantage of the osmotic pressure phenomenon, the expandable lattice providing for the passage of water therethrough, but not for exit of the drug, such as quinidine, propranolol, or nitroglycerine, inside the tablet when the tablet has not been subjected to an osmotic pressure. Unlike tablets with a laser-drilled hole or burstable tablets of the prior art, the expand-_ able lattice of the present invention does not rupture or crack. Instead, the expandable lattice is of a homogeneous polymeric material which, when subjected to osmotic pressure, expands its lattice structure to permit the expulsion of solubilized drug. Confirmation of this mechanism had been experimentally observed through the use of large and small dye molecules, each of a distinctive color. The larger dye molecule was polymerically bonded to be of a very large size. When tablets were formulated with an expandable lattice in accordance with the present invention through an air suspension coating procedure on a Glatt column, having inside the two dye molecules of different colors, it was observed after putting such tablets in water that only the color of the smaller dye molecule diffused out through the "skin" of the tablet into the aqueous envi¬ ronment, i.e., only the color of the smaller dye was observed. The absence of the color of the larger poly¬ merized dye molecule confirmed that the expandable lattice had not ruptured.

In a preferred embodiment, there is provided as the expandable lattice a polymer based upon polyvinyl alco¬ hol and polyethylene glycol (PEG) . The polyvinyl alco¬ hol has a molecular weight generally in excess of about 75,000 and still more preferably in excess of 90,000, and a maximum which is dictated only by the ease of preparation of the polymer, generally about 150,000 being a maximum for practical purposes. In a preferred embodiment, polyvinyl alcohol having a molecular weight of 115,000 is used. The degree of hydrolysis should be relatively high. In a preferred embodiment the degree of hydrolysis should generally be above about 90%, and still more preferably at least 95%. In experiments a degree of hydrolysis of about 98% was found particularly suitable. The polyethylene glycol generally has a molecular weight of from about 400 to about 4000, and still more preferably about 800 to about 1500. In experiments that have been conducted a molecular weight of 1000 has been used.

The relative amounts of the polyvinyl alcohol and the polyethylene glycol may vary greatly, depending upon the properties that are desired of the expanded lattice. In one embodiment, where it is desired to have a polymer coating that will not lose its structural integrity during the extreme osmotic pressure to which it is to be subjected, the polyvinyl alcohol is present generally in a larger amount than the polyethylene glycol, and pre¬ ferably in a weight ratio of polyvinyl alcohol to poly¬ ethylene glycol of about 9:1. In a further embodiment where an at least partial erosion of the expanding lattice is desired for faster release of the drug, a larger percentage of polyethylene glycol is desirable. In one embodiment polyethylene glycol is present at about 20% the weight amount of the polyvinyl alcohol.

The total percentage of polyvinyl alcohol is gener¬ ally from about 5 to 20% by weight (before drying of the polymeric material) , and about 15% being a preferred embodiment. (The "wet" calculation is based upon the maximum concentration in an aqueous medium which still permits full polymer extension and workability) .

The total amount of the polyethylene glycol for an embodiment where no erosion of the polymer lattice is desired will generally be about 1/lOth the weight of the polyvinyl alcohol, e.g., the polyethylene glycol generally be present in an amount of from about 0.1 to about 5% by weight. With erosion being desired, the weight will generally be from about 1 to about 10% polyethylene glycol. With a 15% polyvinyl alcohol content in the first embodiment of the present inven¬ tion, about 1 to about 2% polyethylene glycol is pre¬ ferred, and still more preferably about 1.5% by weight polyethylene glycol.

A lattice enhancer which promotes hydrogen bonding is suitably included in the polymer, including trieth- anolamine, sugars, citrate, tris-hydroxyaminomethane, phosphates, borates, and other hydrogen-bonding cross- linkers. A preferred lattice enhancer is tris-hydroxy¬ aminomethane (TRIS) . TRIS in the amount of from about 0.1 to about 1% is particularly suited.

For organic base drugs it is preferred to have a expandable lattice having a pH-adjustable character. It is therefore advantageous for such basic drugs to have as a lattice enhancer a pH-buffer compound itself, as exemplified by TRIS and triethanolamine. Such lattice enhancers of a basic nature may be used for non-basic drugs as well, and if desired the charge may be neutral¬ ized through use of a salt form. For example, to oper¬ ate at a neutral pH, TRIS hydrochloride would be pre¬ ferred over TRIS itself.

The amount of the drug will be dictated by a consi¬ deration of the total amount that is desired for the period of release taken together with the amount that will be released from the polymeric membrane. It is generally contemplated that the entire amount of the drug may be released in the gastro-intestinal tract.

The degree of rate of expulsion is controlled not only through the selection of the particular polymeric coating components of the expandable lattice, but also through the amount and type of solid material inside the tablet which will affect the osmotic pressure, the osmo¬ tic pressure being a driving force in the determination

of the rate of release of the drug. Small molecules that are pharmaceutically inert may be advantageously included with the drug inside the variably permeable membrane. A sugar such as sucrose may be used or a less soluble sugar such as lactose may be used as examples of embodiments of the present invention, lactose tending to remain in the membrane enclosure for a longer period of time than sucrose, such osmotic pressure helping to push the drug out from the variably permeable membrane.

As an osmotic attractant may be mentioned methocel. Any relatively water insoluble but hygroscopic polymer such as cellulose and cellulose derivatives may be used to replace methocel. Other polymers containing hydra- tion sites may be used. Sucrose is a further preferred osmotic attractrant. A variety of sugars may be used to replace sucrose. A general requirement for the sugar is that the sugar should be on the same order of size as the drug to be delivered. It is also suitable for the sugar to be larger than the drug. It is usually not suitable for the sugar to be substantially smaller than the drug to be delivered, because the mechanism of action of the expandable lattice is such that the osmo¬ tic-mediated expansion of the matrix will expand to allow the sugar to be released, but, if the drug to be delivered is substantially larger than the sugar, then the drug will be retained. Therefore, in expanding the lattice so that the sugar may be released, it is impor¬ tant to keep conditions such that the drug is also released. Among the necessary conditions to cause this to come about is to always insure that the sugar is on the same size or larger than the drug. Magnesium stear- ate may be replaced with other suitable tablet lubricants.

Drug dosage forms, for example, for a drug such as propranolol, may range over wide values. It is proposed to use doses of 25 mg, 50 mg, 100 mg, and 175 mg/tablets in order to achieve necessary therapeutic concentrations required for two times a day dosing. For once a day dosage, a dosage form exactly twice the above sizes would be utilized, having doses of 50 mg, 100 mg, 200 mg, and 350 mg. The release kinetics would be somewhat longer.

Other drugs, such as quinidine, glycerol trini- trate, and theophylline may be administered via the oral dosage form of the present invention in place of pro¬ pranolol.

The following non-limiting example serves to fur¬ ther illustrate the invention:

EXAMPLE I It is desirable to have quinidine bisulfate in a dosage form that releases continuously over 12 hrs. This dosage form would be taken twice daily. In an example, the following is presented:

Per tablet quinidine bisulfate 300 mg Per tablet sucrose in granular form 150 mg Per tablet methalcel 100 mg

(hydroxypropylmeth lcellulose) Per tablet magnesium stearate 5 mg

This combination is used in a conventional tableting form and is pressed into a tablet having a total mass of 555 mg. This tablet is then coated in a suitable gas phase coating column such as a GLATT column. The coating material used is:

Polyvinylalcohol 115,000 mw 9 parts Polyethylene glycol 1,000 mw 1 part The two polymers are dissolved in a mixture of metha- nol:water which is 1:1 v/v. The polymers are dissolved in a me hanol water mixture at a composition of 5% polymer, 95% solvent (range 5-10% polymer) . The tablets are then coated with this solvent mixture in a GLATT column so that 5% of the total tablet mass is coating material (range 2-10%). An average of 27.75 mg of coating material is added to each tablet so that the tablet weight now is 555 mg plus 27.75 mg coating

OMFI material giving a tablet final composition having a mass of 582.75 mg/tablet. Tablets made in the manner just presented give release kinetics over 12 hrs. with a total of 88% release in 12 hrs. giving approximately zero order kinetics.

In order to facilitate the time release of quini¬ dine it may be desired to modify pH constraints within the membrane (polymer film) structure. TRIS (tris- hydroxyamino ethane) may be used in small quantities (0.1 to 3% of the polymer content) in order to facili¬ tate strength and a desired pH environment. TRIS acts both as a pH buffer and as a hydrogen-bonding catalyst. Since TRIS has three hydroxyls and one amine group, it is a suitable molecule for the bridging of hydrogen donors or hydrogen acceptor sites. The same coating system may be used for a variety of medication-contain¬ ing tablets.

EXAMPLE II Propranolol is a well known and widely used drug for cardiac therapy. The major cardiac uses are for ar¬ rhythmias, angina pectoris, and tachycardia. It is also used as a treatment for migraine. Propranolol is used for hypertension. Other conditions related to circula¬ tory or cardiac problems may also be treated with pro¬ pranolol. Propranolol is particularly indicated as a drug for time release since it is generally required for both symptomatic and prophylactic use. It is desirable to maintain a therapeutic concentration of this drug in the blood of patients that require propranolol. Suit¬ able time delivery systems for oral medication for propranolol are twice a day or, in the case of this drug, even once a day. Since propranolol has a biologi¬ cal four to seven hour half-life and does not require an extremely narrow therapeutic concentration range in the blood it may be possible to deliver propranolol on a once a day basis and still achieve adequate therapeutic levels in the blood of the patient throughout the entire time period.

In the following table there is presented a formu¬ lation that is suitable for the time release of pro¬ pranolol for 24 hour therapeutic durations.

Polyvinylalcohol 115,000 mw 9 parts Polyethylene glycol 1,000 mw 1 part The above two components are mixed in methanol water 1:1 v/v at from 5 to 10% polymer content. This is used as a coating material to be applied to a tablet made from the _ propranolol containing tablet in an air phase coating apparatus. The following table gives a listing of the composition of a suitable tablet to be coated for this polymer film coating:

100 mg Propranolol 75 mg Methocel (HPMC)

50 mg Sugar (sucrose, glucose, lactose, etc.) 2 mg Magnesium stearate 2 The above tabular data shows the contents of a film coating and of a propranolol-containing tablet to be coated. The tablet data shown above is for a 100 mg propranolol tablet and would have a total mass of 227 mg. Since the surface to volume of a sphere changes with the square and cube of the radius respectively, there will of course be some adjustment as to the per¬ centage of film coating for tablets of different size. To maintain a constant thickness of polymer coating, in general, as the tablet size reduces the film comprises a higher percentage. In the present case an example of a film coating that is 10% of the total tablet mass is presented. 22.7 mg of film coating are applied to each of the tablets to result in an added mass of 22.7 mg. The final tablet mass is 249.7 mg resulting in a coating of about 9% of the coated tablet mass.

In order to facilitate the time release of a drug, for example, propranolol, it may be desired to modify pH constraints within the membrane (polymer structure. TRIS (tris-hydroxyaminomethane) may be used in small quantities (0.1 to 3% of the polymer content) in order to facilitate strength and a desired pH environment. TRIS acts both as a pH buffer and as a hydrogen-bonding catalyst. Since TRIS has three hydroxyls and one amine group, it is a suitable molecule for the bridging of hydrogen donors or hydrogen acceptor sites. The same coating system may be used for a variety of medication-containing tablets.

EXAMPLE III An oral medical form of nitroglycerin is con¬ structed such that the nitroglycerin is released over a 12-hour period. This medication is composed of a con¬ ventional tablet containing nitroglycerin and is film coated with a polymer coat to effect the release kine¬ tics. The tablet contains 125 parts lactosetriturate (10% glycerol trinate) , 5 parts magnesium stearate, 60 parts sucrose, and 40 parts methocel. Film coating for the glycerol trinitrate: lactose system is treated in the following way. The final mass of this tablet is 252 mg. This tablet is coated with 20 mg per tablet of the polymer coating material:

Polyvinylalcohol 115,000 mw 9 parts Polyethylene glycol 1,000 mw 1 part The final tablet therefore weighs 272 mg resulting in 7.4% coating material. For the tablet given above the coating material polyvinyl alcohol and polyethylene- glycol at a ratio of 9:1 was made up of a 5% concentra¬ tion in methanol water.

Glycerol trinitrate:polyvinyl alcohol triturate may also be used in the formulations given above by simply substituting the glycerol trinitrate:polyvinyl alcohol triturate for the glycerol trinitrate:lactose triturate. The glycerol trinitrate:polyvinyl alcohol triturate is composed of 10% nitroglycerin 90% polymer. The poly¬ vinyl alcohol polymer is generally 10,000 mw 88% hydro- lyzed polyvinylalcohol. In order to facilitate the time release of glycerol trinitrate it may be desired to modify pH constraints within the membrane (polymer film) structure. TRIS (tris-hydroxyaminomethane) may be used in small quan¬ tities (0.1 to 3% of the polymer content) in order to facilitate strength and a desired pH environment. TRIS acts both as a pH buffer and as a hydrogen-bonding catalyst. Since TRIS has three hydrox ls and one a ine group, it is a suitable molecule for the bridging of hydrogen donors or hydrogen acceptor sites. The same coating system may be used for a variety of medica¬ tion-containing tablets.

Claims

WHAT IS CLAIMED IS:

1. An expandable lattice structure which is a film of polyvinyl alcohol and polyethylene glycol having sufficient thickness to retain its structural integrity upon the application of an osmotic pressure and suffi¬ cient thinness whereby said expandable lattice structure is capable of sufficient expansion of its lattice struc¬ ture under the influence of osmotic pressure whereby drug molecules are permitted to pass therethrough.

2. An expandable lattice structure of claim 1, wherein said polyvinyl alcohol has a molecular weight of about 75,000 to about 150,000 and said polyethylene glycol has a molecular weight of from about 400 to about 4,000.

3. A dosage form for oral administration of a drug to a patient which comprises a drug-containing core and a coating of an expandable lattice, said expandable lattice permitting the passage of water therethrough but which under conditions of high pressure is expanded to a state whereby molecules of drug are permitted to pass therethrough, said expandable lattice retaining its structural integrity, said dosage form when contacted with the aqueous medium of the gastro-intestinal tract taking up water in said core through passage of water through said expandable lattice, whereby an osmotic pressure is built up causing said expandable lattice to expand responsive to said osmotic pressure, drug being permitted to escape through the resultant expanded lattice structure of said expandable lattice.

4. A dosage form of claim 1, wherein the drug is quinidine, propranolol or nitroglycerin.

5. A dosage form of claim 3, wherein said core contains an osmotic attractant.