AU9521398A - Controlled drug delivery system for diltiazem - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

PATENTS ACT 1990 COMPLETE

SPECIFICATION

FOR A STANDARD PATENT

ORIGINAL

TO BE COMPLETED BY APPLICANT Nune of Applicant: RANBAXY LABORATORIES LIMITED Actual Inventor(s): V. Nagaprasad; Himadri Sen Address for Service: CALLINAN LAWRIE, 711 High Street, Kew, 3101, Victoria, Australia Invention Title: "CONTROLLED DRUG DELIVERY SYSTEM FOR DILTIAZEM" The following statement is a full description of this invention, including the best method of performing it known to me:- 3/12/98LP10226.CS, CONTROLLED DRUG DELIVERY SYSTEM, FOR DILTIAZEM FIELD OF THE JNVNTION This invention relates to a pharmaceutical composition of a controlled release drug t0 delivery system in the form of tablets or capsules comprising one or more of a. hydrophilic polymer present in amounts greater than 30% about 30 to by weight, an enteric polymer which is present in amounts from about 0.5 to 30%/ by weight and diltiazern or a pharmaceutically acceptable salt or ester thereof in amounts from about 2.5 to 60% by weight, said by weight being based on the tota weight of the composition. The ratio of 13 hydrophilic polymer to enteric polymer is in thc range of about 1:1 to 15:1, such that diltiazemn 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.

BACKGROMN OF THlE INVENTION Diltiazem hydrochloride, a benzothiazepine derivative, 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 required, however, that a drug 23 delivery systcm 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 pH1 in the intestine. Such controlled delivery results in a decrease in the frequency of drug administration thereby improving patient compliance.

Furthermore, controlled drug delivery systems produce constant plasma levels of active ingredients as compared to fluctuations seen when multiple doses of a conventional jA formulation are prescribed. Thus, controlled drug delivery systems may decrease the severity and frequency of side effects.

Several controlled drug delivery systems which are adapted for the delivery of the drug diltiazemn and other drugs are known in the prior art.

U. S. Patent No. 4,894,240 describes a controlled release diltiazecm pellet formulation for once-daily oral administration consisting of a core comprising diltiazem and an organic acid, followed by a multilayer membrane surrounding the core. The membrane comprises a combination of water insoluble polymers and a minor amount of water soluble polymers. The number of layers in the membrane and the ratio of water soluble to water insoluble polymers 0 are formulated so that diltiazemn is released in a controlled manner. A formulation as described by this patent is sold in the United States under the trademark Cardizemn CD' h by Hoechst- Marion-Roussel. Other patents that axe related to the Cardizcmn CD" pellet formulat ion include U. S_ Patent Nos. 5,002,776; 5,286,497; and 5,470,S84. Similar pellet formulations for twice-daily oral administration are disclosed in U. S. Patent No. 4,721,619 and are sold by Hoecbst-Marion-Roussel in the United States under the trademark Cardizem SR:' by Hochbst Marion Roussel.

U. S. Patent No. 4,917,899 discloses a controlled release diltiazeni pellet formulation wherein a core of diltiazem is coated with multiple layers of water insoluble polymers- Slow rclease and fast release pellets are then filled into hard gelatin capsules such that the fast release pellets amount to 15% of the total blend. The formulation releases diltiazem over a 12 hour period such that it is suitable for a twice-a-day oral closing regimen.

U. S. Patent No. 4,839,177 discloses a controlled drug delivery system comprising a core having a defined geomnetry and containing a swellable and/or gellable polymeric materia, 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 arc identified as factors determining the release of the active substane. Such a system is sold in the United States under the trademark Dilacor XRM h by Rhone-Poulenc Rorer. Another patent related to the Dilacor XRM" formulation is U.S. Patent No. 5,422. 123 with the difference being that the support platform described in the latter patent is an elastic support which is slowly soluble or Sellable in aqueous fluids.

U. S. Patent No. 5,529,791 discloses an extended release galenical composition comprising beads containing one or more diltiazemn salts and an effectivc amount of a wetting agent in admixture with one or more diltiazcm salts to maintain thc solubility of diltiazemn in each bead. Thc beads are coated with a microporous membrane comprising at least a water soluble or water dispersible polymer or copolymer, a water-, acid- and base-insoluble polymer, and a pharmaceutically acceptable aduvant.. A formulation as described in this patent is sold in thc United States under the trademark Tiaza by Biovail.

U. S. Patent No. 4,968,507 discloses an osmotic pump comprising a core containing at least one active agent and an osmotic agent surrounded by a water insoluble wall with a defined permeability to water but which is impermeable to solute, and containing at least one p1H insensitive pare forming additive dispersed throughout said wall.

U. S. Patent No. 4,880,631 discloses an osmotic pump similar to that disclosed in U.S.

Patent No. 4,968,507 (discussed below) but specifically containing diltiazern-L-nialate as the active ingredient. A formulation as described by this patent is sold in the United State undecr the trademark Tiaznate' by Merck Co.

European Patent App. No. 373,417 discloses a sustained release diltiazem once-daily tablet formulation with the drug dispersed in a hydrophobic matrix comprising one or more of ethylcellulose, a mixtuire of mono- and diglycerides, cellulose acetate, calcium phosphate, cellulose acetate butyrate and microcrystalline cellulose. Further, the document describes a water solubic coating comprising a swelling hiydrophilic polymer or a barrier coating comprising a water-insoluble polymer, an enteric polymer or a mixture thereof.

European Patent App. No. 381,181 discloses a core containing diltiazem. or other iC active agent and an osmotically active substance. coated by a semni-permeable wall forming material.

U. S. Patent No. 4,792,452 discloses a controlled release pharmaceutical formulation comprising a drug, a pH-dependent polymer which is an alginic acid salt, a p1--independent hydrocolloid gelling agent and a binder. The formulation is Wa2 ion free. The drug is released independent of the pH of the environmnt.

U. S. Patent No. 4,946,686 describes a solubility modulated drug delivery system in which the core is comprised of a water soluble drug and a controlled release solubility modulator which is either a complexing agent or a surfactant. The core is surrounded by a water insoluble microporous wall containing pore forming additives.

U. S. Patent No. 4,994,273 describes a solubility modulated drug delivery system in which the core is made of a water soluble drug and a solubility modulating agent comprising a complexing agenit or a surfactant. The core is surrounded by a water insoluble semipermeable wall.

U. S. Patent No. 4,968,508 discloses 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 between about 5.0 to about 7.4. The total weight of the polymers is less than 30% by weight of the system. The cefaclor is released within a few hours and is suitable for the administration of cefaclor twice daily.

U. S. Patent No. 5,000,962 discloses a long acting diltiazem tablet comprising more than 35% by weight of a sweliable hydrophilic, polymer, a binder, a lubricant and diluent.

Both coated and uncoated tablets arc disclosed.

U. S. Patent No. 5,578,321 discloses a tablet. containing diltiazem hydrochloride suitable for once-daily oral admidnistration. The tablet comprises not less than 30% by weight diltiazemn hydrochloride and from 30% to 70% by weight hydroxypropyl methylcellu lose having a number average molecular weight of at least 50,000.

The present invention provides a controlled drug delivery composition for onecc-daily administration of diltiazern to a human subject, the composition comprising diltiazem, one or more hydrophilic, polymers, and an enteric polymer, wherein the ratios and amouis of enteric polymer and hydrophilic polymers are such that diltiazem is released at a constant rate over a range of pH. Enteric or pH-dependent polymers are insoluble at the acidic pH- of the stomach but dissolve and/or erode in the higher p11 range of about 5 to 8 encountered in the intestine.

Therefore, at the lower pH in the stomach, enteric polymers impede drug release. At the higher pH in the intestinc, the enteric polymers dissolve and/or erode- Thu.% in spite of the higher solubility of the drug in acidic fluids, it is. released. at more or Ies the same rate throughout the pii range likely to be encountered in the gastrointestinal tract In addition to the use of a combination of defined ratios of hydrophilic and enteric polymers, the use of a high quantity of polymers in the present invention contributes towards ensuring a constant rate of release of the drug and therefore a uniform and consistent absorption. Effective plasma levels arc maintained for a period as long as 24 liro and persist near the minimum effective level for up to 30 hrs. This further ensures uniform blood level profiles and eliminates the risk of overdose. Such an elimination of risk of overdose is of particular concern in once-daily formulations as they contain a quantity of active medicament whir-h is several times the conventional dose of the medicamnent.

The release of a drug from a matrix system -is dependent on the physiochernical nature of the drug, and the present invention provides a composition comprising hydrophilic. and enteric polymers in ratios and amounts that results in controlled release of diltiazemn at a rate that benefits therapy with diltiazern.

The present invention is easy to produce. Prior art processes arc either more time consuming or expensive, F~or example, the process for making the coated pellets in capsules such as Cardizem CD"' that are described in U. S. Patent 4,894,240, and the drug delivery system of Dilacor X M described in U. S. Patent 4,839,177, are complex and expensive to make.

BRIEF DESCRIPTION OF THLE DRIAWING Figure I shows a linear plot of mean serum diltiazem concentration v~rsp.s time in healthy malie human subjects who have been admxinistered the pharmaceutical composition of the present invention and a reference diltiazem product (Dilacor X~) SUMMARY-OF TIRE INVENTION This invention is directed to a controlled release pharmaceutical composition in the form of tablets or capsules comprising about 30 to about 97% by weight of one or more hydrophilic polymers, about 0.5 to about 30% by weight of an enteric, polymer, and about to about 60% by weight of diltiazem or a pharmaceutically acceptable salt or ester thereof.

The ratio of hydrophilic polymer to eneric polymer is from about 1:1 to about 15:1. This formulation allows the diltiazem to be released at a rate such that effective plasma levels of diltiazem arc maintained over a period of twenty-four hours after administration to human subjects.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a matrix of well mixed components comprising diltiazem or its pharmaceutically acceptable salt or ester, one or more hydrophilic polymers, an enteric polymer and pharmaceutically acceptable excipients. The pharmaceutical composition is either compressed into tablets or graniulated and filled into capsules.

Suitable hydrophilic polymfers include cellulose ethers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, or other water soluble or swellable polymers such as sodiumn carboxymethyl cellulose, xanthan gum, acacia, tragacanth gum, guar gum, karaya gum, alginates, gelatin, albumin and the likc. These hydrophilic polymers also include polyacrylate polymers, such as honiopolymers based on acrylic acid cross-linked with allyl sucrose or allyl pentaerythritol, or copolymners based on acrylic acid and long chain allyl acrylates cross-linked with allylpentaeythritol. The polyacrylate polymers may be used alone or in admixture with cellulose cthers sucb as methylcellulose, hydroxypropyl mcthylceflulose, hydroxypropylccllulosc, hydroxyethyleellulose, and the like. According to the invention, the hydrophilic polymcrs are present in amounts ranging from about 30% to about by weight of the systcm.

The preferred hydrophilic polymers are selected from the group consisting of cellulose others such as hydroxypropyl metbylcellulose, hydroxypropylcollulosc, methylceihilose and mixtures thereof.

According to a preferred embodiment of the present invention, the hydrophilic, polymer is a mixture of a hydroxypropyl methyiccilulose whose 2% by weight aqueous solution has a viscosity greater than 10,000 cPs, and hydroxypropylc ellulose whose 2% by weight aqueous solution has a viscosity less tha 5000 r-Ps. The hydroxypropyl methylcellulose may be present in amounts from about 10% to 70% by weight, preferably from about to 30% by weight, of the total weight of the system. The hydroxypropylcdllulose may be present in amounts from about 5% to 50% by weight, preferably from about 15% to 25% by weight, of the system.

Examples of hydroxypropyl xnethylccllulose polymers that may be used in the present invention include those available from Dow Chemidcal Co. under the brand namie Methocel, such as, Methocel K15K, Methocel KIOOM, and the like. Elycroxypropylceflulosc polymers that may be used in the present invention include, for example, those available under the S brand name Kiucel' from Aqualon and HPC' available from Nippon Soda 0o,, such as HPC-

L

T

N, HPC-M

M

Klucel OF", Kiucel Jr' h Kiucel HF' and the like.

The enteric polymers that may be used in the present invention include polyacrylate copolymers such as Methacrylic Acid Copolymer, USP/NF, Types A, B or C, which are available from Robi GmnbH under the brand name Eudragit"; cellulose derivatives, such as cellulose acetate phithalate, hydroxypropyl methylWollulose phthalata, hydroxypropyl methylcellulose acetate succinate; and polyvinyl acetate phthaatc and the like.

In a preferred embodiment of this invention, the enteric polymer is a polyacrylate enteric polymer. The enteric polymer is present in amounts from about 0.5% to 30% by weight of the system. In a further preferred embodiment of the invention, the enteric polymer is present in amounts from about 0.5% to 10% by weight of the system.

According to another preferred embodiment of the invention, the total weight of the hydrophilic polymers and enteric polymers is in the range of about 35% to 97.5% by weight of the system.

The present invention may also contain pharmaceutically acceptable excipients such as diluents, binders, lubricants, buffering agents, preservatives, stabilizers, surfactants, colorants and the like. The system may be formed into tablets, as dosage form, by conventional means, or into granules or cohesive slugs by conventional means, and the granules or slugs thus prepared may be filled into capsules. Optionally, the tablets may bc coated or one or more tablets imay be fihle'4 into one capsule in order to improve the pharmaceutical quality attributes such as tastc and appeaance.

A preferred method of preparing the composition of this invcntion comprises sifing the drug, polymers and diluents; followed by mixing them with about one-half of the lubricants. The well mixed mass is then compacted into slugs and then granulated by screening. The granules are lubricated with the second half of the lubricants and then compressed into tablets. The tablets are then illed into capsules.

The invention is further illustrated by the following examples: EXAMPLE 1 This example illustrates the process of making the pharmaceutical composition of the is invention in the form of compressed tAblets.

Table I (Formulation 1) -H-ydroxypropylcellulose (CM)100 7.

Mapne-sium Stearate 6 T ao 8 (1.4) Acrosi-200 (Colloida sifficn ioxic) 6 T-Otal 590 (100.0)-

I

Diltiazern hYdrochloride-, Eudragit L-100, Mcthocel K-100-M, hydroxypropylcellulose- M and lactose in the amounts shown in Table 1 were screened through a No- 60 mesh (British Standard Sieve ("BSS");250 The screened mass along with half the quanlitics of magnesium stearate, talc and Acrosil-200 were mixed together for 15 minutes. The well mixed components were compressed into slugs using a 16 station tablet press. The slugs were sized through a No. 22 mesh (BSS;7 10iium). The resulting: granules, were lubricated with the remaining half of magnesium stearate, talc and Aerosil and then compressed into capsuleshaped tablets using standard concave punches and 15.2x6.7mm dies on a 16-station tablet Press.

L0 The release of diltiazem from thiese tablets was evaluated using USP Type II apparatus in a dissolution medium consisting of 0.1N HCI in one test, and a pH 6.8 phosphatc buffer in the second test. The paddle speed was 100rpm. The results are given in Table 2.

TABLE 2 (TM RkCEN RELEASE _M8 OAN Hip11 .8uffer 2 1 4. (.0 4 2M. (54) -8 49.6 64 49-53.3 14 __70.9 57.8 *Figures in parenthesis indicate percent coefficient of variation.

The low percent coefficient of variation indicates uniformity and reproducibility of release of diltiazem from the tablets. The results also indicate that the rate of release of diltiazcm from the drug delivery system was not appreciably affected by the pH of the dissolution medium.

EXAMPLE 2 This cxaxnple illustrates the proecm of making the pharmaceutical composiiorn of the invention in the form of Multiple tablets filled into capsulei.

Table 3 (Formulation 2) The granules were prepared from the ingredients in the amounts shown in Table 3 in the 3a=e manner as in Example 1 and then compressed into 180mg.tablets using flat bevelled punches and dies on a 16 station tablet press. four such tablets we e,,ilgd into each of size '00' capsules.

The release of diltiazem from these capsules was evaluated as described in Example 1, and the results are given in Table 4.

TABLE 4 Time (Hrs.) Vereent Release* ON HUI -pH 6.8 Huffer 39 2 319 13 26-87(4.0) 14 07(-)44.2(3.4) 877.5 74.

-12 -93.1 87A47 (5.7) Tigures in Paren esis i cate percent coe cient of variation.

The low percent± coefficient of variation indicates uniformity and reproducibility of release of diltiazem from. the capsules. The results also indicate that the rate of release of diltiazern from the drug delivery system was not appreciably affected by the pH of the dissolution medium.

EXAMPLE 3 This example illustrates the process of makdig the pharmaceutical composition of the invention in the form of tablets filled into capsules.

Table 5 (Formulation 3) Ingemtg/ ta let(0oWIW) HtiaernFly-ro--Morde 4 (40.0) tL -560( 115 22.5) HydroxypropylelluIose (HPC-M 1

W

3.3) Magnesium Stcarate al c13 Aerosil 6 ]U Total 600(100.0 Granules were prepared from the ingredients shown in Table 5 in the same marnner as described in Example 1 except that for granulation of the powder wnass in this example, roll compaction replaced slugging on a tablet press. Thc granules were compressed into tablets using 19.0 x 6.2mmn capsule shaped punches. Each tablet was filled into a si ngi size '0' capsule.

The release of diltiazeni from these capsules was evaluated as described in Example 1, and the results arc given in Table 6.

TABLE 6 TiePcr. ercent Reloale* UNfl pH 6. Buffer__ 2 21.63-(6.4) 15.93 (TY.O) 4 33.87 27.03 8 5287.(3:T 46.70 (07)- T -68.0 -62.63 (0.75) Fiue nprrfi-i ndct ecn niu of variation.

The low percent coefficient of variation indicates uniformity and reproducibility of release of diltiazern from the capsules. The results also indicate that the rate of release of diltiazm from the drug delivery system was not appreciably affected by the pH of the dissolution medium.

For each of the formulations of Examples I to 3, at least six tablcts were tested for dissolution. Overall, more than two hundred tablets were rnade in accordance with the present invention and were tested for-dissolution. The physical integrity of the mix 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 hydrophilic swelling polymer and less than 30% by weight of the enteric polymer in the syst~em. Thus, there was low variability in rate of release and risks of dose dumping are virtually eliminated.

A formulation in the form of a single tablg in a capsule prepared according to the prcsent invention was evaluated in-vivo in 6 young healthy male volunteers in comparison to a referenc-e product (Dilacor XR T 240mg capsule). The test and reference formulations were administ .ered as a singi 240mg dose. Concentrations of diltiazem in serum up to a period of 36 hrs post-administration were measured. The serum concecntration vs time profile for the reference and the test products are given in Figure Controlled release formulations, in certain instances, may give a slow onset of action. However, it is evident from Figure 1 that the diltiazemn formulation prepared according to the present invention gives effective absorption within a short period such that minimum effective plasma levels (50 ng/ml) are achieved within 2 hrs. Peak plasma levels are achieved in about 5 hours. Furthermore, it is e .vident that effective levels between 50 ng/ini to 200 ug/mi are maintained up to 24 brs. and persist near the minimum effective level for up to 30 brs.

While the invention has been described by reference to specific examples, this was for purposes of illustration. Numerous alternatives will be apparent to those skilled in the art and are considered to be within the scope of the invention.

Claims (11)

1. A controlled, releas PharMaecical w*mpoSt'aD, cOMPrising; about 3010o about 917% by weight of a hydrophilic polymer. about 0.5 to about 30% by weight of an entaiic polymer. and about 2.5 to about 60% by wtigba of diltazeM or a ph===acutically acceptable salt or cstar tbereof wherein the ratio of hydrophilic polymer to enteric polymner is in Ibe range of about 1; 1 to about 15: 1.

2. The pbannaccutical composition of claim 1, whmein do~ hydrophilic poLymer ccwpise~a cellulose ether.

3. The pharmaceutical composilloni of claim 2. wherein th z cellulose ethe is selected from the -group consisting of methylcellulosq, hydro~yropyl zncthyloellulosc, hydroxypropyllllose, hydroxyethylcellulose and mixtures thereof.

4. The phanmaeeiitical. composition of clim 1. wherein the hydrophiliz polymer comprises a mixinre of a hydroxypropyl metlxyloollulose whose 21% by wecight aqueous solution has a viscosity greate than 10,000 cPs, and a hydzoxypropylceihlosc whose by weight aqueous solution h2as a viscosity less than 5000 CJs.

The pharmnaccuatical composition of claim 1. wherein the bydrophilic polymer comprises a mixture of about 10%/ to about 701/ by weight of tiydroxypropyl metbylcellulose aud about 5% to about 00/, by weight of hydroxypropyllulose

6. The phxmcelatical pcom itilon of CIl 1, wherein tbe hydropic POly~r~c comprises a mixture of about 20%/ to about 30%/ by Wd$,ht of h~ydroypTopyl MetY~cd1olslO and about 15% to about 259/ by weigt of hydroaCFpIPYldUloSi-

7. The phamazcttc8 1 CoomswtOf ofcaim 1, wherein the enteric polymer is a polyacrylate Polymer.

S. The -phaz~wCui~cal compogitol of rglaim 1, wheriu the entel~r polymer C'ompriseS 0.5% to abovt 305Ao bY WeI&b Of the compOsitiofl-

9. -Me phawMaGCQtc,2coImpOSitoI1 of claim 1. wkzereiD the eitcerc Polymcr Comitfses about 0.5 1o about 101/ by weight of lbel compOsition'

10. The ph~zTmaeUtical comPOiOofcamI wherein ftb total weihtof hydroplirl polymer and entefir, ioye s in be jange of about 350/s wo~bout 973%

11. The PharmacG utir' co poitOI of cldim I in the fo=m of a tablet OT a capsule- DATED this 3rd day of December,

1998. RANBAXY LABORATORIES LIMITED By their Patent Attorneys: CALLINAN LAWRIE e 4 L- Na