This invention relates to a process for the preparation of controlled release drug formulation containing diltiazem or its pharmaceutically acceptable salt as active ingredient.
Diltiazem hydrochloride is a calcium channel blocker used in the treatment of angina and hypertension. The solubility of diltiazem significantly decreases as the pH increases in the gastrointestinal tract. It is however required that the delivery system deliver the drug at a constant rate as it is transported from the region of low pH in the stomach to a region of higher pH in the intestine.
US Patent No 4,894,240 described a controlled release diltiazem pellet formulation for once-daily administration consisting of a core comprising of diltiazem and an organic acid, followed by a multilayer membrane surrounding the core, the membrane comprising a combination of water insoluble polymers and minor proportion of water soluble polymers. The number of layers in the membrane and the ratio of water soluble to water insoluble polymers were such that diltiazem was released in a controlled manner.
US Patent No. 4,917,899 disclosed a controlled release diltiazem pellet formulation wherein core of diltiazem was coated with multiple layers of water insoluble polymers. Slow release and fast release pellets were then filled into hard gelatin capsules such that the fast release pellets amounted to 15% of the total blend. The formulation controlled the release over a 12 hour period such that it could be administered twice daily.
US Patent No. 4,839,177 disclosed a controlled drug delivery system comprising of a core containing a swellable and/or gellable polymeric material and a suitable platform containing a water insoluble polymeric material applied to the core in the form of a partial coating. The intensity and duration of the swelling force and the geometry of the device were identified as factors determining the release of the active substance.
European Patent No. 381,181 disclosed a core containing diltiazem or active agent and osmotic active substance coated by a semipermeable wall forming material.
US Patent No 4,792,452 disclosed a controlled release pharmaceutical formulation comprising the drug, pH-dependent polymer which is alginic acid salt, a pH-independent hydrocolloid gelling agent and a binder. The formulation was Ca+2 ion free. Drug was released independent of the pH of the environment.
US Patent No. 4,968,508 disclosed a matrix tablet formulation for cefaclor, .comprising from about 5% by weight to about 29% by weight of hydrophilic polymer, and from about 0.5% by weight to about 25% by weight of an acrylic polymer which dissolves at a pH in the range of about 5.0 to about 7.4. The total weight of the polymers was less than 30% by weight of the system.
The technologies adopted in the known art as stated herein thus include use of an organic acid buffered core to maintain higher solubility of the drug in the system, use of swelling force of a polymer to control release, use of osmotic pressure to control release and use of a pH responsive matrix containing a mixture of enteric polymers and hydrophilic polymers.
The present invention envisages the preparation of a controlled release formulation of the drug diltiazem with hydrophilic polymers and enteric polymers such that the said polymers are more than 35 % by weight of the formulation. The ratios of enteric polymers and hydrophilic polymers are such that diltiazem is released at a constant rate over a range of pH. In addition to obtaining constant release, an added benefit of the system is that the use of a high quantity of polymers in our invention reduces the variability in rate of release of drug and ensures uniform and consistent absorption upto as long as 20 hrs. This further ensures uniform blood level profiles and eliminates the risk of dose dumping. Such an elimination of risk of dose dumping is of particular concern in once daily formulations as they contain a quantity of active medicament which is several times the conventionaldose of the medicament.
Accordingly the present invention provides a process for the preparation of sustained release drug formulation containing diltiazem which process comprises mixing diltiazem or its pharma-ceutically acceptable salt from 2.5 to 69.5 % by weight, a hydrophilic polymer as herein described, in an amount more than 30 % by weight and an enteric polymer as herein described from 0.5 to 30 % by weight, the ratio of hydrophilic polymers to enteric polymer is 1:1 to 15:1 such that diltiazem is released at a rate that allows effective plasma levels of diltiazem to be maintained over a period of twenty four hours post-administration to human subjects, if desired, mixing with the drug formulation conventional pharmaceutically acceptable excipients such as herein described to form tablets or granules or slugs.
The hydrophilic polymers used in the preparation of the drug formulation are cellulose ethers such as hydroxypropyl methyl-cellulose, hydroxypropyl cellulose or other water soluble or swellable polymers such as sodium carboxymethyl cellulose, xanthan gum, acacia, tragacanth gum, guar gum, karaya gum, alginates,gelatin,albumin and the like. The preferred hydrophilic polymers are cellulose ethers such as hydroxypropylmethyl-cellulose, hydroxypropylcellulose, methylcellulose or mixtures thereof.
The other hydrophilic polymers used are homopolymers based on acrylic acid cross-linked with allyl sucrose or allylpentaeryth-
ritolor copymers based on acrylic acid and long chain (C10- C30) alkylacrylates and cross-linked with allylpentaerythritol either alone or admixed with cellulose ethers such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxy-ethylcellulose.
According to a preferred embodiment of the present invention, the hydrophilic polymer is a mixture of high viscosity (>10,000 cps) and low viscosity (<5000 cps) grades of polymers selected from the class of cellulose ethers.
According to a particular preferred embodiment, the mixture of high viscosity and low viscosity grades of cellulose ethers is used in combination with polyacrylate enteric polymers.
The enteric polymers used in the preparation of the drug formulation may include polyacrylate copolymers such as Methacrylic Acid Copolymers, USP/NF (United States Pharmacopoeia / National Formulary), Type A, B or C; cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthaiate, hydroxypropyl methylcellulose acetate succinate; or polyvinylacetate phthalate. The enteric polymers are present at a concentration from 0.5% to 30% by weight of the formulation. These polymers are insoluble at an acidic pH of the stomach but dissolve and/or erode in the pH range from about 5 to about 8. Therefore, at the lower pH in the stomach they impede drug release. At the higher pH, the enteric polymers dissolve. Thus, inspite of the higher solubility of the drug in acidic fluids, it is released at more or less the same rate throughout the pH range likely to be encountered in the gastrointestinal tract.
According to one preferred embodiment of the invention, the total weight of the hydrophilic polymer and enteric polymer is more than 35% by weight of the formulation.
According to another preferred embodiment of the invention, the enteric polymer comprises 2.5 to 30% by weight of dilt|azem.
The drug formulation prepared according to the present invention may be mixed with the conventional pharmaceutically acceptable excipients such as diluents, binders, lubricants, buffering agents,-preservatives, stabilizers, surfactants, colours and the like and then formed into tablets, as dosage form, by conventional means or formed into granules or cohesive slugs, by conventional means and the granules or slugs prepared are filled into.capsules. Optionally, the tablets may be coated or filled into capsules. Filling of tablets into capsules or coating of tablets helps in masking the bitter taste of a medicament.
A preferred method of carrying out the pesent invention consists of sifting the drug, hydrophilic polymers, enteric polymers and diluents, followed by mixing them with half of the lubricants. The well mixed mass may then be compacted into slugs and then granulated by screening. The granules may be lubricated with the second half of the lubricants and then compressed into tablets.
Other methods of carrying out the invention could involve granulation with an appropriate solvent such as isopropanol or ethanol, with or without water.
The present invention is further illustrated by the following examples which are not intended to limit the effective scope of the invention claimed.

EXAMPLE 1
This example illustrates the process of making the drug formulation according to the present invention in the form of compressed tablets.
Formulation 1
(Table Removed)
Diltiazem hydrochloride, Eudragit L-100, Methocel K-100-M, hydroxypropyl cellulose (medium viscosity grade), and lactose were screened through No.60 mesh (250pm) screen. The screened mass along with half the quantities of magnesium stearate, talc, and Aerosil were mixed together for 15 minutes. The well mixed components were compressed into slugs using a 16 station tablet press. The slugs were then granulated by sizing through a No 22 mesh (710um)screen. The granules were lubricated with the remaining half of magnesium stearate, talc and Aerosil, and then compressed into capsule shaped tablets using standard concave punches and 15.2x6.7mm dies on a 16 station tablet press.
The release of diltiazem from these tablets was evaluated using USP Type II apparatus in a dissolution medium consisting of 0.1 N HCl in one test and pH 6.8 phosphate buffer in the second test. The paddle speed was 100rpm. The results are given in Table 1.
Table 1

(Table Removed)
* Figures in brackets indicate percent coefficient of variation.

The low percent coefficient of variation indicates uniformity and reproducibility of release of diltiazem from the tablets.
EXAMPLE 2
This example illustrates the process of making the drug formulation according to the present invention in the form of multiple tablets in capsules.
Formulation 2
(Table Removed)
The granules were prepared as in example 1 and then compressed into 180mg tablets using flat bevelled punches and 7.0mm dies on a 16 station tablet press. Four tablets were filled into size 'OO' capsules.
The release of diltiazem from these capsules was evaluated as described in example 1, and the results are given in Table 2 :
Table 2
(Table Removed)
* Figures in brackets indicate percent coefficient of variation.
The low percent coefficient of variation indicates uniformity and reproducibility of release of diltiazem from the capsules.

EXAMPLE 3
This example illustrates the process of making the drug formulation according to the present invention in the form of tablets in capsules.
Formulation 3
(Table Removed)
Granules were prepared as described in example 1 except that for granulation of the powder mass in this example roll compaction replaced slugging on a tablet press. The granules were compressed into tablets using 19.1 x 6.3mrrrcapsule shaped punches, and tablet filled into size 'O' capsules.
The release of diltiazem from these capsules was evaluated as described in example 1, and the results are given in Table 3 :
Table 3
(Table Removed)
* Figures in brackets indicate percent coefficient of variation.
The low percent coefficient of variation indicates uniformity and reproducibility of release of diltiazem from the capsules.

Dissolution test was performed on more than two hundred unity made within the stated claims of the invention. The physical integrity of the units was maintained throughout the period of dissolution, demonstrating that none of the units showed physical failure. This is attributable to the use of more than 30 % by weight of the enteric polymer present in the formulation. Thus there was low variability in rate of release and risk OF dosedumping are virtually eliminated.
The formulation in the form of single tablet in a capsule prepared according to the present invention was evaluated in-vivo in young healthy male volunteers in comparison to a reference produce (Dilacor XR 240 mg capsule). The test and reference formulations were administered as a single 240mg dose. The concentrations oi diltiazem in serum upto a period of 24 hrs post-administration were measured. The serum concentration time profile for the reference (R) and the test (T) products is given in Figure 1, shown in the attached drawings. Controlled release formulation, is certain instances, may give a slow onset of action, however, it is evident from Figure 1 that the diltiazem formulation prepared according to the present invention gives effective absorption within a short period such that minimum effective plasma levels (50ng/ml) are achieved within 2 hrs. Peak plasma levels are achieved in about 5 hrs. Furthermore it is evident that effective levels between £0ng/ml to 200ng/ml are maintained upto 24 hrs and persist near the minimum effective level for upto 30 hrs.
The controlled release drug formulation, prepared according to the
present invention, is not a mere admixture but has properties
which are different from the sum total properties of its
ingredients.

We Claim
1. A process for the preparation of Controlled release drug formulation containing diltiazem comprising of mixing diltiazem or its pharntaceutically acceptable salt from 2.5 to 69.5 % by weight, a hydrophilic polymer as herein described in an amount more than 30 % by weight and an enteric polymer as herein described from 0.5 to 30 % by weight, the ratio of hydrophilic polymers to enteric polymer is 1:1 to 15:1 such that diltiazem is released at a rate that allows effective plasma levels of diltiazem to be maintained over a period of twenty four hours post-administration to human subjects, if desired, mixing with the drug formulation conventional pharmaceutically acceptable excipients such as herein described to form tablets or granules or slugs.
2. A process as in claim 1, wherein the hydrophilic polymers is selected from the class of cellulose ethers such as methyl-cellulose, hydroxypropyl methyl cellulose, hydroxypropyl-cellulose, hydroxyethylcellulose or mixtures thereof.
3. A process as claimed in claim 1, wherein the hydrophilic polymers are homopolymers based on acrylic acid cross-linked with allyl sucrose or allylpentaerythritol or copolymers based on acrylic acid and long chain (C10-C30) alkyl acrylates and cross-linked with allylpentaerythritol alone or in admixture with cellulose ethers such as methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose or hydroxyethylcellulose.
4. A process as claimed in claims 1 to 3, wherein the hydrophilic polymers is a mixture of high viscosity (>10,000 cps) and low viscosity (<5000 cps) grades of polymers selected from the class of cellulose ethers.
5. A process as claimed in claim 1, wherein the enteric polymer is selected from polyacrylate copolymers such as Methacrylic acid copolymers, USP/NP Type A, B, C or from other polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate or polyvinyl acetate phthalate or cellulose acetate butyrate.
6. A process as claimed in claims 1 to 5 wherein the total weight of hydrophilic polymers and enteric polymer is more than 35 % by weight of the formulation.
7. A process as claimed in claims 1 to 6 wherein the enteric polymer comprises from 2.5 to 30 % by weight of diltiazem or its pharmaceutically acceptable salt.
8. A process as claimed in claims 1 to 7 wherein the drug formulation prepared is mixed with the conventional pharma-ceutically acceptable excipients such as herein described and formed into tablets, as dosage form, by conventional means.
9. A process as claimed in claims 1 to 8 wherein the drug formulation prepared is mixed with the conventional pharma-ceutically acceptable excipients such as herein described and formed into granules or cohesive slugs by conventional means and the granules or slugs filled into capsules.
10. A process for the preparation of controlled release drug formulation containing diltiazem substantially as herein described and illustrated by the examples herein.