The present invention relates to a once-a-day sustained release formulation of diltiazem comprising blend of delayed release and fast release pellets of diltiazem in a unit dose containment system.
Chemically, Diltiazem is cis-(+)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one. It is a benzothiazine derivative possessing calcium antagonist activity. Diltiazem blocks the influx of calcium ions in smooth and cardiac muscle and thus exerts potent cardiovascular effects. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris and myocardial ischemia and hypertension, while displaying a low incidence of side effects.
Conventional diltiazem tablets need to be administered three or four times daily, such frequent drug administration may reduce patient compliance and produce irregular blood levels. Consequently, adverse therapeutic effects can arise. There is therefore a need for a diltiazem formulation that ensures that diltiazem blood levels remain relatively stable over long periods of time without the need for frequent administration.
U.S. Pat. Nos. 4,721,619, 4,891,230, 4,917,899 and 5,219,621 disclose diltiazem formulations that purport to require administration once every twelve hours (i.e., twice a day). U.S. Pat. Nos. 4,894,240, 5,002,776 and US 5,286,497 disclose diltiazem formulations that purport to require administration once every 24 hours (i.e., once a day). To obtain the dissolution profiles disclosed in these patents, the formulations disclosed require a multi-layer membrane that coats the central core and an organic acid in the active core and/or in the multi-layer membrane. According to the aforementioned patents, the pellets must be dried for a number of hours during and after the coating process. This procedure increases the overall manufacturing cost. Additionally, the organic acid included in such formulations may have an irritating effect on administration. Accordingly, a need exists for a sustained release diltiazem formulation for once a day administration having desired in-vitro and in-vivo release profile, which does not have an irritating effect, and which can be economically and industrially manufactured.
Our scientists have now formulated a sustained release formulation of diltiazem, for once-a-day administration, which is free of organic acids and is bioequivalent to commercially available Cardizem CD® capsules.
Hence in one general aspect, there is provided a bioequivalent sustained release formulation of diltiazem comprising blend of delayed release and fast release pellets of diltiazem in a unit dose containment system, wherein the pellets are free of organic acid.
In another general aspect, there is provided a bioequivalent sustained release formulation of diltiazem comprising blend of delayed release and fast release pellets coated with one or more pH independent polymers, wherein the pellets are free of organic acid.
In another general aspect, there is provided a bioequivalent sustained release formulation of diltiazem comprising delayed release pellets which comprise from about 20 to about 30%w/w of the polymeric coating and fast release pellets which comprise from about 5 to about 16%w/w of the polymeric coating by weight of the drug layered pellets, wherein the pellets are free of organic acids
In another general aspect, there is provided a bioequivalent sustained release formulation of diltiazem comprising from 30 to 70% of delayed release pellets and from 30 to 70% of fast release pellets in a unit dose containment system, wherein the pellets are free of organic acids.
In another general aspect there is provided a process for the preparation of a bioequivalent sustained release formulation of diltiazem, wherein the process comprises the steps of;
(a) layering the dispersion of diltiazem, polymeric binder and one or more pharmaceutically inert excipients on to the inert cores to form drug layered pellets;
(b) layering the dispersion of one or more pH independent polymers with one or more pharmaceutically inert excipients on to the drug layered pellets of step
(a) till the weight gain of about 20 to about 30%w/w, to form delayed release pellets;
(c) layering the dispersion of one or more pH independent polymers with one or more pharmaceutically inert excipients on to the drug layered pellets of step (a) till the weight gain of about 5 to about 16% w/w, to form fast release pellets;
(d) mixing the pellets of delayed release pellets of step (b) and fast release pellets of step (c); and
(o) filling the mixture of step (d) into unit dose containment system.
In another general aspect, there is provided a method of treating hypertension in mammals, which comprises administering to a mammal in need thereof, a bioequivalent sustained release formulation of diltiazem.
The term "bioequivalent" as used herein refers to pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions. The FDA considers two products bioequivalent, if the 90% CI of the relative mean Cmax, AUC(o-t) and AUC(0-) of the test to reference (e.g. innovator) is within 80.00% to 125.00% in the fasting state. The sustained release formulation of diltiazem of the present invention is bioequivalent to the commercially available Cardizem CD® capsules.
The term "unit dose containment system" as used herein includes capsule, sachets, tablets and the like.
The term "diltiazem" as used herein includes diltiazem free base as well as pharmaceutically acceptable acid addition salts thereof, particularly the hydrochloride salt, enantiomers, hydrates, metabolites, and prodrugs. The amount of diltiazem may vary from about 60 mg to about 420 mg in a unit dose containment system. Further the ratio of amount of diltiazem in the delayed release pellets to fast release pellets may vary from 0.3:0.7::0.7:0.3, in particular 1:1.
The term "inert core" as used herein is either a commercially available product or prepared in the laboratory. The inert core may be of any geometric shape, though
spherical beads are preferred for the ease of uniform coating. The inert cores may be selected from pharmaceutically inert insoluble, soluble or swellable material. The insoluble inert cores are composed of sand (silicon dioxide), glass, microcrystalline cellulose or plastic (polystyrene) material. On the other hand soluble inert cores are composed of sugar selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and the like. The swellable inert cores are composed of hydroxypropyl methylcellulose.
The term "pharmaceutically inert excipients" as used herein may include all physiologically inert additives used in the pharmaceutical art of dispensing. Examples include binders, diluents, surfactants, disintegrants, lubricants/glidants, plasticizers, coloring agents, and the like.
Specific examples of binders include but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxyethyl cellulose, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, and zein, in particular hydroxypropyl methylcellulose.
Specific examples of diluents or fillers include lactose, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, kaolin, starch, and the like.
Specific examples of surfactants include sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include those containing long chain cations, such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine or the like. Suitable non-ionic surfactants include polyoxyethylene sorbitan fatty acid esters, fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols; polyglycolized glycerides such as Gelucire; polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, cholesterol, and the like.
Specific examples of disintegrants include sodium carboxymethyl cellulose, low-substituted hydroxypropylcellulose L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, starch, partially pregelatinized starch, and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Specific examples of plasticizers include acetyltributylcitrate, triethylcitrate, acetylated triacetin, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, tributylcitrate, glyceroltributyrate, polyethyleneglycol (molecular weight of from 380 to 420), propylene glycol and the like.
Coloring agents includes any FDA approved color for oral use.
The polymeric coating on diltiazem pellets is responsible for giving the diltiazem pellets its particular controlled release characteristics (i.e. delayed release or a fast release pellet). The polymeric coating of the delayed release pellet and the fast release pellet may be manufactured from different materials. Alternatively, they may be manufactured from the same material, but differing amounts of the polymeric coating are utilized to produce the desired dissolution profile. Delayed release pellets comprise from about 20 to about 30%w/w, in particular from about 22 to about 28%w/w, of the polymeric coating and fast release pellets comprise from about 5 to about 16%w/w, in particular from about 6 to about 12%w/w, of the polymeric coating, by weight of the drug layered pellets.
The polymeric coating comprises one or more pH independent polymers and pharmaceutically inert excipients.
Examples of the pH independent polymers include but not limited to ethyl cellulose, cellulose acetate, cellulose acetate butyrate, or an acrylic copolymer such as Eudragit RS 30D; RS 100; NE 30D; RL 30D or RL 100. A preferred material is an acrylate copolymer which has a permeability which is independent of pH. Such a preferred acrylate copolymer is commercially available as Eudragit RS 30D which is available as a 30 wt. % aqueous dispersion of copolymers of acrylic and methacrylic acid esters, having a number average molecular weight of 150,000 with a low content of quaternary ammonium groups.
The drug layered pellets of the present invention may be prepared by coating the diltiazem on an inert core or by other conventional means such as extrusion-spheronisation, rotogranulation, co-acervation or alternatively by precipitation from
solution techniques.
In one of the embodiment, a sustained release formulation of diltiazem may be prepared by a process comprising the steps of:
(a) preparing the dispersion of diltiazem, polymeric binder, and one or more pharmaceutically inert excipients in a suitable solvent;
(b) layering the dispersion of step (a) on to the inert cores to form drug layered pellets in a air suspension coater;
(O preparing the dispersion of one or more pH independent polymers with one or more pharmaceutically inert excipients in a suitable solvent;;
(d) layering the dispersion of step (c) on to the drug layered pellets of step (b) till the weight gain of about 20 to about 30%w/w, to form delayed release pellets in a air suspension coater;
(c) layering the dispersion of step (c) on to the drug layered pellets of step (b) till
the weight gain of about 5 to about 16% w/w, to form fast release pellets in a
air suspension coater;
(0 mixing the pellets of delayed release pellets of step (d) and fast release
pellets of step (e); and (g) filling the mixture of step (f) into capsule of suitable size.
Examples of suitable solvents include water and organic solvents such as isopropyl alcohol, ethanol, n-butanol, octanol and the like.
To form the active core, any suitable apparatus can be used and include an air suspension coater such as Wurster coater, rotor granulator, pan coater spheronizer and extruder. The coating can be applied to the active cores using a conventional coating pan, Wurster coater, an automated system such as a CF granulator, for example a FREUND CF granulator, a GLATT fluidized bed processor, an AEROMATIC, a modified ACCELA-COTA or any other suitably automated bead coating equipment.
The pellets may be filled into hard or soft gelatin capsules. The pellets may also be compressed into tablets using a binder and/or hardening agent commonly employed in tabletting techniques such as microcrystalline cellulose sold under the trademark AVICEL or a co-crystallized powder of highly modified dextrins (3% by weight) and sucrose sold under the trademark DI-PAC in such a way that the specific dissolution rate of the pellets is maintained.
The invention is further illustrated by the following example, which is for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.
Example 1
Drug layered pellets

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Procedure
1. The weight of all the ingredients were checked.
2. Hydroxypropyl methyl cellulose was added to the isopropyl alcohol with continuous stirring so that no lumps were formed.
3. Sodium lauryl sulphate was dissolved in purified water.
4. Solution of step 3 was added to the solution of step 2 and stirred for 10 minutes.
5. Diltiazem hydrochloride was slowly added to solution of step 4 so that no lumps were formed.
6. The dispersion of step 5 was passed through BSS#60.
7. Sugar spheres were loaded in Wurster coater and drug layering was performed using dispersion of step 6
8. The pellets were dried in Wurster coater till LOD was less than 3%w/w.
9. The drug layered pellets of step 8 was sifted using appropriate sieves to remove aggregation and fines.
Fast release pellets

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10. Talc and acetyl tributyl citrate were dispersed in purified water with continuous stirring.
11. Eudragit RS 30D was added to dispersion of step 10 with continuous stirring.
12. The dispersion of step 11 was passed through BSS # 60 (250 microns).
13. Drug layered pellets of step 9 were loaded in Wurster coater and coated with dispersion of step 12 till the weigh build is 7% of drug layered pellets.
14.The pellets of step 13 were dried in Wurster coater till LOD (105°C/10 minutes) is less than 3%w/w.
15. The dried pellets of step 14 were sifted using appropriate sieves to remove aggregates and fines.
16. Talc was sifted through #30BSS (500 microns) and used to lubricate the fast release pellets of step 15 in V-blender for 10 minutes.
17.The fast release pellets of step 16 were cured in a tray drier at 40°C for an appropriate time.
Delayed release pellets

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18. Talc and acetyl tributyl citrate were dispersed in purified water with continuous stirring.
19. Eudragit RS 30D was added to dispersion of step 18 with continuous stirring.
20. The dispersion of step 19 was passed through BSS # 60 (250 microns).
21. Drug layered pellets of step 9 were loaded in Wurster coater and coated with dispersion of step 20 till the weight build is 25% of the drug layered pellets.
22.The pellets of step 21 were dried in Wurster coater till LOD (105°C/10
minutes) is less than 3%w/w. 23. The dried pellets of step 22 were sifted using appropriate sieves to remove
aggregates and fines. 24.Talc was sifted through #30BSS (500 microns) and used to lubricate the
delayed release pellets of step 23 in V-blender for 10 minutes. 25.The delayed release pellets of step 24 were cured in a tray drier at 40°C for
an appropriate time.
Mixing of fast release and delayed release pellets
26. The fast release pellets of step 17 and delayed release pellets of step 25 were mixed in V-blender for 15 minutes.
27. The mixture of pellets of step 26 was filled in capsule of suitable size.
In-vitro studies
In-vitro drug release from the capsules prepared as per the composition given in example 1 was determined by dissolution for diltiazem using USP II dissolution apparatus at 100 rpm, in 900 ml of 0.1NHCI. The results of the release studies along with the marketed formulation Cardizem CD® are represented in the table 1 below.
Table 1: In-vitro cumulative percentage of diltiazem release

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Also, in-vitro release from the fast release pellets of example 1 was determined by dissolution for diltiazem using USP II dissolution apparatus at 100 rpm, in 900 ml of 0.1NHCI and is represented in table 2 below.
Table-2 In-vitro cumulative percentage of diltiazem release from the fast release pellets

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In vivo Bioequivalence study
In vivo performance of Diltiazem capsules prepared as per the composition of Example 1 was evaluated with respect to the Cardizem CD® capsules in 9 and 12 healthy male volunteers under fasting and fed conditions respectively. The study protocol followed was an open randomized, three-treatment, three-period, three-sequence, single-dose, crossover, with a wash out period of 10 days. Blood samples were collected at appropriate time intervals over a period of 59.00 hours and diltaizem content analyzed using a validated in-house HPLC method. Pharmacokinetic parameters Cmax (Maximum plasma concentration), AUC1 (Area under the plasma concentration at time t) and AUCα (Area under the plasma concentration at infinity) were calculated from the data obtained. The results of the studies are given in Table 3.
Table 3: Bioequivalence Data

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As evident from the data, the diltiazem capsule of example 1 is bioequivalent to the Cardizem CD® capsules.

WE CLAIM:
1. A bioequivalent sustained release formulation of diltiazem comprising blend of delayed release and fast release pellets of diltiazem in a unit dose containment system, wherein the pellets are free of organic acid.
2. The bioequivalent sustained release formulation as claimed in claim 1, wherein delayed release and fast release pellets are coated with one or more pH independent polymers.
3. The bioequivalent sustained release formulation as claimed in claim 2, wherein the pH independent polymers is selected form the group consisting of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, or an acrylic copolymer such as Eudragit RS 30D; RS 100; NE 30D; RL 30D or RL 100.
4. The bioequivalent sustained release formulation as claimed in claim 3, wherein the pH independent polymer is Eudragit RS 30D.
5. The bioequivalent sustained release formulation as claimed in claim 1, wherein the delayed release pellets comprise from 20 to 30%w/w of the polymeric coating by weight of the drug layered pellets.
6. The bioequivalent sustained release formulation as claimed in claim 1, wherein the fast release pellets comprise from 5 to 16%w/w of the polymeric coating by weight of the drug layered pellets.
7. The bioequivalent sustained release formulation as claimed in claim 1, wherein the fast release pellets release from 60 to 100%w/w of diltiazem after 3 hours when measured in 900ml of 0.1NHCI in USP II apparatus at 100 rpm.
8. The bioequivalent sustained release formulation as claimed in claim 1, wherein the formulation further comprises pharmaceutically inert excipients selected form the group consisting of binders, diluents, surfactants, disintegrants, lubricants/glidants, plasticizers, coloring agents, and the like.
9. The bioequivalent sustained release formulation as claimed in claim 1, wherein the formulation is prepared by a process comprising the steps of:
(a) layering the dispersion of diltiazem, polymeric binder and one or more pharmaceutically inert excipients on to the inert cores to form drug layered pellets;
(b) layering the dispersion of one or more pH independent polymers with one or more pharmaceutically inert excipients on to the drug layered pellets of step (a) till the weight gain of about 20 to about 30%w/w, to form delayed release pellets;
(c) layering the dispersion of one or more pH independent polymers with one or more pharmaceutically inert excipients on to the drug layered pellets of step (a) till the weight gain of about 5 to about 16% w/w, to form fast release pellets;
(d) mixing the pellets of delayed release pellets of step (b) and fast release pellets of step (c); and
(e) filling the mixture of step (d) into unit dose containment system.
10. The bioequivalent sustained release formulation of diltiazem and process of preparation thereof, as described and illustrated in the examples herein.