WO2014002015A1

WO2014002015A1 - Pharmaceutical composition comprising dutasteride

Info

Publication number: WO2014002015A1
Application number: PCT/IB2013/055221
Authority: WO
Inventors: Sumit Madan; Ravinder Singh; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2012-06-25
Filing date: 2013-06-25
Publication date: 2014-01-03

Abstract

The present invention relates to a pharmaceutical composition comprising dutasteride and a process for the preparation thereof. The composition is useful for the treatment of patients with benign prostatic hyperplasia (BPH).

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING DUTASTERIDE

Field of the Invention

The present invention relates to a capsule dosage form comprising dutasteride and a process for the preparation thereof. The composition is useful for the treatment of patients with benign prostatic hyperplasia (BPH).

Background of the Invention

Presently, 5-alpha-reductase inhibitors are used worldwide for the treatment of benign prostatic hyperplasia. 5-alpha-reductase inhibitors such as finasteride and dutasteride reduce the size of the prostate, thereby alleviating the static component of bladder outlet obstruction.

Dutasteride, chemically defined as (5a, 17 )-N- {2,5-bis (trifluoromethyl)phenyl}- 3-oxo-4-azaandrost-l-ene-17-carboxamide, is a 5-alpha-reductase inhibitor. Dutasteride alone is used to inhibit conversion of testosterone to dihydrotestosterone (DHT), the androgen primarily responsible for the enlargement of prostate gland.

Development of dutasteride compositions is subject to many formulation constraints. Dutasteride has poor solubility. These solubility challenges can affect bioavailability, possibly resulting in reduced or unpredictable bioavailability. The choice of excipients is important in order to ensure good solubility and good bioavailability of the pharmaceutically active compound.

In order to ensure enhanced bioavailability of dutasteride dosage forms, solubilizers and permeability enhancers are required to be used in large amounts leading to an increase in the size of the dosage form. The commercially available soft gelatin capsules of dutasteride 0.5 mg contain solubilizers in an amount of around 350 mg, leading to larger sized capsules. The larger capsule size poses greater potential safety issues such as choking, formulation arrest, and prolonged transit time, which could result in esophageal injury and/or pain. The larger formulation size also raises product efficacy concerns due to patient's inability or unwillingness to swallow the larger formulations. Further, a large amount of excipients may lead to undesired side effects

(http://www.health24.com/Medical/Meds-and-you/Using-medicines/Inactive-ingredients- in-meds-can-cause-side-effects-20120721). Since geriatric patients constitute the main patient group for dutasteride formulations, there exists a need in the art to develop a more patient-compliant dosage form which is smaller in size and easy to administer.

Soft gelatin encapsulation provides the potential to improve the bioavailability of pharmaceutical agents. Relatively insoluble active ingredients can be dispersed in a liquid or gelled carrier to provide faster absorption upon rupture of the capsule. Further, it may be useful to include an antioxidant in the composition so as to prevent oxidation of the pharmaceutically active ingredients in the composition. The other advantages of soft gelatin capsules include superior patient compliance/consumer preference (ease of swallowing, appealing appearance, absence of objectionable taste, and convenience), pharmaceutical elegance, excellent dose uniformity, better tamper evidence (tampering leads to puncturing and visible leakage), and safer handling of highly potent or cytotoxic drug compounds.

Another challenge in formulating compositions comprising dutasteride is that dutasteride is prone to oxidation. Therefore, gelatin capsule formulations are preferred as they are much more resistant to oxidation due to the low oxygen permeation of typical gelatin shells, and further have better bioavailability.

Solubilizers which absorb too much water from the ambient air lead to liquefaction of the solid formulation and unwanted crystallization of the active ingredients. A highly hygroscopic solubilizer may also cause problems in processing the dosage forms.

Further, the use of solubilizers might give a negative sensoric effect to the final formulation (tackiness, oiliness, or waxiness, depending on the type and on the used percentage). Additional drawbacks could be related to handling, if the solubilizer needs heating and/or stirring to have a homogeneous product before use, or gel formation that might occur during the production process. Other disadvantages could be strong coloring, bad color, and loss of viscosity.

Some solubilizers may exhibit toxicity when used in large amounts. Hence, the choice of solubilizer and the amount used is critical in formulating a dutasteride dosage form.

PCT Publication No. WO 99/08666 discloses gelatin capsules filled with a solution comprised of a therapeutically effective amount of a pharmaceutically active aza steroid and a fatty acid ester of glycerol or propylene glycol. PCT Publication No. WO 99/08684 discloses a gelatin capsule filled with a therapeutically effective amount of a pharmaceutically active aza steroid, polyethylene glycol, and propylene glycol.

U.S. Patent No. 5,565,467 discloses dutasteride and its method of use.

Dutasteride compositions comprising a large amount of solubilizer and permeability enhancer lead to enhanced composition weight, and hence larger size of the final dosage forms, which are not patient compliant. There exists a need in the art to develop a more patient-compliant dutasteride dosage form having lesser amounts of excipients so that it is smaller in size, and yet achieves similar bioavailability.

Summary of the Invention

In one aspect, the present invention relates to a capsule dosage form comprising dutasteride, wherein the total fill weight is equal to or less than about 200 mg.

In one embodiment, the total fill weight is equal to or less than about 100 mg.

In another embodiment, the capsule dosage form of the present invention is a soft gelatin capsule.

In another embodiment, the fill composition of the capsule dosage form comprises dutasteride and a solubilizer.

In another embodiment, the fill composition of the capsule dosage form comprises dutasteride, a solubilizer, an antioxidant, and optionally other pharmaceutically acceptable excipients.

In another embodiment, the ratio of dutasteride to solubilizer in the fill composition ranges from about 1 :400 to about 1 :50.

In another embodiment, the ratio of dutasteride to solubilizer in the fill composition is about 1 :200.

In another embodiment, dutasteride is present in a concentration of about 0.025% to about 2.5% by weight of the fill composition.

In another embodiment, the present invention relates to a soft gelatin capsule comprising: (i) dutasteride, (ii) glyceryl caprylate/caprate, and (iii) butylated

hydroxytoluene, wherein the total fill weight is equal to or less than about 100 mg. In another embodiment, the dutasteride capsule dosage form of the present invention shows a comparable dissolution profile and is bioequivalent to the innovator's formulation Avodart^®.

In another aspect, the present invention relates to a process for the preparation of a capsule dosage form comprising dutasteride, wherein the process comprises the steps of: a) heating the solubilizer and adding one or more pharmaceutically acceptable excipients under stirring to form a solution;

b) dissolving dutasteride in the solution of step a) while stirring;

c) filling the solution of step b) into soft gelatin capsules.

In another aspect, the present invention relates to a method of treating benign prostatic hyperplasia (BPH) by administering a capsule dosage form comprising dutasteride, wherein the total fill weight is equal to or less than about 200 mg.

In one embodiment, the present invention relates to a method of treating benign prostatic hyperplasia (BPH) by administering a soft gelatin capsule composition comprising: (i) dutasteride, (ii) glyceryl caprylate/caprate, and (iii) butylated

hydroxytoluene, wherein the total fill weight is equal to or less than about 100 mg.

In another embodiment, the dutasteride composition is administered in combination with another active ingredient in the same dosage form or in a different dosage form.

In another aspect, the present invention relates to a pharmaceutical composition comprising a capsule dosage form of dutasteride and a dosage form of an additional active ingredient.

In one embodiment, the additional active ingredient is an ai receptor antagonist such as tamsulosin, alfuzosin, terazosin, prazosin, or doxazosin in an immediate -release form or a modified-release form.

In another embodiment, the pharmaceutical composition is a hard gelatin capsule comprising a dutasteride soft gelatin capsule and an alfuzosin extended-release tablet.

In another embodiment, the pharmaceutical composition is a hard gelatin capsule comprising a dutasteride soft gelatin capsule and tamsulosin extended-release tablet/delayed- release granules. The details of one or more embodiments of the inventions are set forth in the description below. Other features and objects of the invention will be apparent from the description and examples.

Brief Description of the Drawings

Figure 1 depicts the in-vivo dutasteride profile of the test and reference product under fed conditions.

Figure 2 depicts the in-vivo dutasteride profile of the test and reference product under fasting conditions.

Detailed Description of the Invention

The present invention relates to a capsule dosage form comprising dutasteride, wherein the total fill weight is equal to or less than about 200 mg, more particularly equal to or less than about 100 mg. Reduced fill weight leads to a smaller sized dosage form, and hence improves patient compliance. The marketed soft gelatin capsule has a fill weight of not less than 350 mg, and hence is of a larger size leading to poor patient compliance. Further, a larger amount of solubilizer may lead to undesired side effects.

The capsule dosage form of the present invention may be a hard gelatin capsule or a soft gelatin capsule. Preferably, the capsule is a soft gelatin capsule.

The fill composition of the capsule dosage form of the present invention comprises dutasteride, a solubilizer, an antioxidant, and optionally other pharmaceutically acceptable excipients.

The term "about", as used herein, when used along with the values assigned to certain measurements and parameters means a variation of up to 10% from such values, or in case of a range of values, means up to a 10% variation from both the lower and upper limits of such ranges.

The term "dutasteride" refers to dutasteride free base. Dutasteride is preferably present in a concentration of 0.025% to 2.5% by weight of the fill composition, more preferably from 0.05% to 1.0% by weight of the fill composition.

Suitable solubilizers used in the present invention are selected from the group consisting of oils such as corn oil, peanut oil, safflower oil, soya bean oil, or Miglyol^® 812 (neutral oil, triglycerides of medium chain fatty acids); propylene glycol mono- or di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, or propylene glycol caprylic-capric acid diester (e.g. Miglyol^® 840); polyalkylene glycol such as polyethylene glycol 400-600; dimethylsulfoxide; or mixtures thereof. The preferred solubilizer is mono-diglycerides of caprylic and capric acid (e.g. Capmul^® MCM). The composition of Capmul MCM is a mixture of fatty acid esters of glycerol and is approximately 95% monoester, 1% glycerin, 2% free fatty acid, and less than 0.5% water, and is derived from approximately 85% caprylic acid and 15% capric acid (all percentages are weight percents).

The ratio of dutasteride to solubilizer in the fill composition ranges from about

1 :400 to about 1 :50 and more particularly is about 1 :200. The marketed formulation contains drug and solubilizer in a ratio of about 1 :700. Hence, the amount of solubilizer is significantly reduced in the present invention without affecting the bioavailability of the dosage form.

Suitable antioxidants are selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, or mixtures thereof. A particularly preferred antioxidant is butylated hydroxytoluene. The antioxidant or mixture of antioxidants is preferably present in a concentration of from about 0.001% to about 0.5% by weight of the total dosage form.

The pharmaceutically acceptable excipients may be selected from one or more of dispersing agents, plasticizing agents, surfactants, colorants, fragrances, and preservatives.

Dispersing agents are generally used to ensure appropriate uniformity using viscosity, while providing a pharmaceutically elegant appearance to the resulting solution. Suitable dispersing agents are selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cyclodextrin, or mixtures thereof.

Plasticizers are especially useful with soft gelatin capsule preparations because, without them, capsules tend to harden and lose their beneficial properties by potentially cracking or becoming brittle. Suitable plasticizing agents are selected from the group consisting of glycerin, propylene glycol, sorbitol, or mixtures thereof.

The surfactant is preferably a non- ionic surfactant. Suitable surfactants are selected from the group consisting of macro gel esters (e.g. Labrafils^®), Span^® 80, Gelucires , tocopheryl polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, or mixtures thereof.

Suitable preservatives are selected from the group consisting of parabens such as methylparaben, propylparaben, isopropylparaben, butylparaben, and isobutylparaben, and their salts such as sodium butylparaben; benzoic acid and its salts and esters; benzyl alcohol; urea derivatives such as diazolidinyl urea or imidazolidinyl urea; DMDM hydantoin; sorbic acid and its salts; or mixtures thereof.

Suitable colorants and fragrances may be used, provided that they are compatible with the fill composition, the gelatin of the softgel capsule, and the dispensing container.

Soft gelatin capsule shells can be produced according to any of the acceptable methods known in the art for production of such capsules. The soft gelatin shells may comprise from about 20% to about 80% gelatin. The gelatin can be of Type A, Type B, or a mixture thereof. The soft gelatin shells may also comprise a plasticizer. Suitable plasticizers include glycerin, xylitol, sorbitol, polyglycyerol, non-crystallizing solutions of sorbitol, glucose, fructose, glucose syrups, or mixtures thereof. Preferably, the plasticizer is glycerin. The soft gelatin shells of the instant invention may also comprise water and other ingredients, such as taste modifiers, coloring agents, preservatives and moisture retaining agents.

Suitable taste modifiers include non reducing sugars such as xylitol, maltitol (e.g. Lycasin^®), or mixtures thereof. Suitable preservatives include methylparaben, propylparaben, or mixtures thereof. Suitable moisture retaining agents include celluloses, cellulose derivatives, starches, starch derivatives, vegetable gums, non-hygroscopic, mono-, di-, and oligosaccharides, silicon dioxide, or mixtures thereof. Various FD&C coloring agents may be used to impart the desired color to the capsule.

The present invention provides a process for the preparation of a capsule dosage form comprising dutasteride. The process comprises the following steps:

a) heating the solubilizer and adding one or more pharmaceutically acceptable excipients under stirring to form a solution;

b) dissolving dutasteride under stirring in the solution of step a);

c) filling the solution of step b) into soft gelatin capsules. The composition of the invention may be used in treating conditions such as benign prostatic hyperplasia (BPH). The pharmaceutical composition of the present invention may be administered in combination with other active ingredients in the same dosage form or different dosage forms. The other active ingredients are those effective in the treatment of benign prostatic hyperplasia, and include but are not limited to, on receptor antagonists such as tamsulosin, alfuzosin, terazosin, prazosin, and doxazosin in immediate-release or modified-release form.

The present invention also encompasses a pharmaceutical composition comprising a capsule dosage form of dutasteride in combination with a second dosage form of an additional active ingredient. The additional active ingredients are those effective in the treatment of benign prostatic hyperplasia, and include but are not limited to, on receptor antagonists such as tamsulosin, alfuzosin, terazosin, prazosin, and doxazosin in an immediate-release or a modified-release form. Preferably, the additional active ingredient is alfuzosin or tamsulosin.

The second dosage form may be an immediate-release or a modified-release dosage form. Preferably, the second dosage form is a modified-release dosage form such as alfuzosin extended-release tablets, tamsulosin extended-release tablets, or tamsulosin delayed-release granules.

The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.

EXAMPLES

Example 1

Brief Manufacturing Process:

1. Glyceryl caprylate/caprate was heated and butylated hydroxytoluene was added to while stirring, and then the solution was cooled.

2. Dutasteride was added to the solution of step 1 under continuous stirring to obtain the dutasteride mixture.

3. The dutasteride mixture of step 2 was filled into a soft gelatin capsule.

Dissolution Studies

The pharmaceutical composition of Example 1 was compared with the marketed formulation of dutasteride (Avodart^® soft gel capsules) for the release profile in OGD media (0.1N HCl with Pepsin (1.6g/L) and 4% w/v SLS) using USP apparatus II at 50 rpm in 900 mL media and were found to have the following release profile:

Table 1

As is evident from the above data in Table 1 , the test product and the reference product have comparable dissolution profiles.

Pharmacokinetic Studies Under Fed Conditions

The pharmaceutical composition of Example 1 was compared with the marketed formulation of dutasteride (Avodart^® soft gel capsules) under fed conditions on 12 healthy adult male subjects.

Values for various pharmacokinetic parameters, including observed C_max and AUCo-_twere calculated and are provided in Table 2 below.

Reference (R): Avodart^® capsules 0.5 mg (Dutasteride 0.5 mg)

Test (T): Dutasteride 0.5 mg (Example 1)

Table 2: Comparative Pharmacokinetic Data for Dutasteride Capsules of Example 1 (T) and Adovart^® (R) in 12 Healthy Adult Human Male Subjects:

• Average T_max values for both the test and reference are 4.92 hours and 5.08 hours, respectively, which indicate a comparable absorption pattern.

• The T/R ratio for the rate of absorption (C_max) observed was 97.22% with an intra-subject CV of 19.9%. The confidence intervals (CI) were also well within range of 80% to 125%.

• The extent of drug absorption (AUC) was comparable between the test and reference products as evident from the T/R ratios obtained, i.e., 95.71% for AUCo-72. The confidence intervals were also well within the range.

Conclusion: As is evident from the above data in Table 2, the test product and reference product are bioequivalent. Pharmacokinetic Studies Under Fasting Conditions

The pharmaceutical composition of Example 1 was compared with the marketed formulation of dutasteride (Avodart soft gel capsules) under fasting conditions on 14 healthy adult male subjects.

Values for various pharmacokinetic parameters, including observed C_max and

AUCo-t were calculated and are provided in Table 3 below.

Reference (R): Avodart^® capsules 0.5 mg (Dutasteride 0.5 mg)

Test (T): Dutasteride 0.5 mg (Example 1)

TABLE 3: Comparative Pharmacokinetic Data for Dutasteride Capsules of Example 1 (T) and Adovart^® (R) in 14 Healthy Adult Human Male Subjects:

• Average T_max values for both the test and reference are 2.08 hours and 2.02 hours, respectively, which indicate a comparable absorption pattern.

• The T/R ratio for the rate of absorption (C_max) observed was 1 12.0% with an intra-subject CV of 15.3%. The confidence intervals were also well within range of 80% to 125%.

• The extent of drug absorption (AUC) was comparable between the test and reference products as evident from the T/R ratios obtained, i.e., 107.52% for AUCo-72. The confidence intervals were also well within the range.

Conclusion: As is evident from the above data in Table 3, the test product and reference product are bioequivalent. Example 2:

Brief Manufacturing Process:

A. Alfuzosin Hydrochloride ER Tablets

1. Alfuzosin hydrochloride, lactose anhydrous, colloidal anhydrous silica, and povidone were sifted and blended.

2. Talc and magnesium stearate were sifted and added to the blend of step 1 and further blended.

3. The blend from step 2 was compacted in a roller compactor and milled to obtain alfuzosin lactose granules.

4. The alfuzosin lactose granules of step 3, lactose anhydrous, povidone, colloidal anhydrous silica, and hydroxypropyl cellulose were blended, followed by the addition of hydroxypropyl methylcellulose, talc, and magnesium stearate, and further blended.

5. The blend of step 4 was compressed using appropriate tooling to obtain tablets.

B. Dutasteride Soft Gels

6. Glyceryl caprylate/caprate was warmed and butylated hydroxytoluene was dissolved in it, followed by the addition of dutasteride under mechanical stirring.

7. The dutasteride mixture obtained in step 6 was filled into soft gelatin

capsules.

C. Capsule Filling

8. The alfuzosin tablet obtained in step 5 and the dutasteride soft gel capsule obtained in step 7 were filled into a hard gelatin capsule to obtain the final composition. Example 3 :

Brief Manufacturing Process:

A. Tamsulosin Hydrochloride Extended-Release Tablet

1. Polyethylene oxide (WSR 301) and polyethylene oxide (WSR 303) sifted together and polyethylene glycol 6000 was sifted separately. 2. The material of step 1 was transferred to a rapid mixer granulator and was dry blended.

3. Tamsulosin hydrochloride was dissolved in isopropyl alcohol under

sonication/stirring until a uniform dispersion was obtained.

4. The material of step 2 was granulated using the solution of step 3 and was dried and sieved.

5. Colloidal anhydrous silica and the dried granules of step 4 were blended together followed by the addition of magnesium stearate.

6. The blend of step 5 was compressed using appropriate tooling to obtain tablets.

7. Opadry^® white was dispersed in an isopropyl alcohol-methylene chloride mixture.

8. The tablets of step 6 were coated using the Opadry^® dispersion of step 7.

B. Dutasteride Soft Gelatin Capsules

9. Glyceryl caprylate/caprate was warmed and butylated hydroxytoluene was dissolved in it, followed by the addition of dutasteride under mechanical stirring.

10. The dutasteride mixture obtained in step 9 was filled into soft gelatin

capsules.

C. Capsule Filling

1 1. The tamsulosin tablet obtained in step 8 and the dutasteride soft gel capsule obtained in step 10 were filled into a hard gelatin capsule to obtain the final composition. Example 4:

^Λ 250 mg dispersion is equivalent to 75 mg solid content.

^ΛΛ Extra added to compensate for loss at 80% coating efficiency. Target weight build up is 9.5 mg per capsule.

** Lost during processing.

Brief Manufacturing Process:

A. Tamsulosin Hydrochloride MR Pellets

1. Macrocrystalline cellulose was sifted and mixed with tamsulosin hydrochloride solution in warm purified water.

2. Magnesium stearate was sifted and mixed with the material of step 1 in a mixer.

3. The material of step 2 was granulated with Eudragit^® L 30 D-55 to obtain the desired wet mass. The wet mass was extruded and spheronized.

4. The pellets of step 3 were dried and enteric coated with a dispersion of methacrylic acid-ethyl acrylate copolymer in purified water.

5. The coated pellets were sifted and mixed with purified talc.

B. Dutasteride Soft Gelatin Capsules

6. Glyceryl caprylate/caprate was warmed and butylated hydroxytoluene was dissolved in it and cooled, followed by the addition of dutasteride under mechanical stirring.

7. The dutasteride mixture obtained in step 6 was filled into soft gelatin capsules.

C. Capsule Filling

8. The tamsulosin pellets obtained in step 5 and the dutasteride soft gel capsule obtained in step 7 were filled into a hard gelatin capsule to obtain the final composition.

Claims

We claim:

1. A capsule dosage form comprising dutasteride, wherein the total fill weight is equal to or less than about 200 mg.

2. The capsule dosage form according to claim 1 , wherein the total fill weight is equal to or less than about 100 mg.

3. The capsule dosage form according to claim 1, wherein the dosage form is a soft gelatin capsule.

4. The capsule dosage form according to claim 1 , wherein the fill composition comprises dutasteride, a solubilizer, an antioxidant, and optionally other pharmaceutically acceptable excipients.

5. The capsule dosage form according to claim 4, wherein the ratio of dutasteride to solubilizer in the fill composition ranges from about 1 :400 to about 1 :50.

6. The capsule dosage form according to claim 4, wherein the ratio of dutasteride to solubilizer in the fill composition is about 1 :200.

7. The capsule dosage form according to claim 4, wherein the dutasteride is present in a concentration of from about 0.025% to about 2.5% by weight of the fill composition.

8. The capsule dosage form according to claim 1, wherein the dosage form is a soft gelatin capsule comprising: (i) dutasteride, (ii) glyceryl caprylate/caprate, and (iii) butylated hydroxytoluene, wherein the total fill weight is equal to or less than about 100 mg.

9. A process for the preparation of a capsule dosage form comprising dutasteride, wherein the process comprises the steps of:

a) heating a solubilizer and adding one or more pharmaceutically acceptable excipients to form a solution;

b) dissolving dutasteride in the solution of step a);

c) filling the solution of step b) into soft gelatin capsules.

10. A method of treating benign prostatic hyperplasia (BPH) by administering a capsule dosage form comprising dutasteride, wherein the total fill weight is equal to or less than about 200 mg.

11. The method of treating benign prostatic hyperplasia (BPH) according to claim 10, by administering a soft gelatin capsule composition comprising: (i) dutasteride, (ii) glyceryl caprylate/caprate, and (iii) butylated hydroxytoluene, wherein the total fill weight is equal to or less than about 100 mg.

12. A pharmaceutical composition comprising a capsule dosage form of dutasteride and a dosage form of an additional active ingredient.

13. The pharmaceutical composition according to claim 12, wherein the additional active ingredient is an ¾ receptor antagonist such as tamsulosin, alfuzosin, terazosin, prazosin, or doxazosin in immediate-release or modified-release form.

14. The pharmaceutical composition according to claim 12, wherein the

pharmaceutical composition is a hard gelatin capsule comprising a dutasteride soft gelatin capsule and an alfuzosin extended-release tablet.

15. The pharmaceutical composition according to claim 12, wherein the

pharmaceutical composition is a hard gelatin capsule comprising a dutasteride soft gelatin capsule and tamsulosin extended-release tablet/delayed-re lease granules.