Field of Invention:

Modified release preparations are those that provide an In-vitro release profile (a "modified release) of an active ingredient, such as a pharmaceutically active ingredient, that is different from the in vivo release profile of the active ingredient without the modification (an 'immediate release1). The modified release may be such as a delayed, extended, pulsed or sustained release. The modification of the release may be desired for a number of reasons, such as for minimising the side effects of the drug or for decreasing the frequency of dosing to improve patient compliance.

As with all pharmaceutical preparations, an important aspect of the manufacture is their consistency and stability of the product. Typically, a modified release product is linked to two aspects; firstly, the stability of the ingredients themselves, namely the maintenance of their intended drug release, chemical, microbiological, therapeutic and toxicological properties over time; and secondly, consistency in forming manufacturing. The present invention is directed towards both this aspects of stability and consistency.

However, it has been found for some modified release preparations in storage, the release profile alters by a significant amount. For example, some delayed release preparations that have been formulated with an enteric coating so as to release only small amounts of active (10% or less) after 20 minutes might release up to 80% of active by 20 minutes after the preparation has been stored. This increase in rate of release can detract from the utility and effectiveness of the product.

In conventional manufacturing process, drug release will vary from batch to batch due to variabilities in manufacturing like drug reservoir unevenness and polymer layer thickness( Fig-1).

It is an aim of the present invention to provide a modified release preparation that is consistent and stable, in that the release profile after storage of a preparation in accordance with the invention will be substantially the same as the release profile of the preparation before storage.

Summary of the invention:

The present invention provides manufacturing of modified release products by using direct spraying technique by loading a solution of drug and polymers mix on to a suitable spherical core under optimized instrumental conditions, thereby each drug molecule is uniformly covered with polymers and gives consistent quality product.

The invention can be applied for many low percentage and organic soluble products to achieve consistent quality product.

In this type of composition, the active principle dissolved in the solution and is dispersed or coated over the pellets. The release of the active principle from the solution is achieved by contact of biological fluids with the said pellets. More specifically, biological fluids migrate through the polymer layers and dissolve the active principles and the latter are released by diffusion through the layers or by erosion principle, drug is released into the biological fluids.

As above, these compositions are generally obtained by granulation, by a wet or solvent route, and then compression, involving high proportions of each of the constituents.

The aim of the invention is thus to provide a novel process for the manufacture of a pharmaceutical composition Use of direct spraying solution to manufacture modified release dosage form has an object of significantly decreases number of excipients and manufacturing operations, thus making it possible to obtain a formulation which is simple to employ, low cost and re-producible.

Thus the main objective of this invention is stability and consistency. Another object is to simplify the process to achieve stability and consistency. Yet another object is that this method can be applied for many low percentage and organic soluble products to achieve consistant quality products.

Description of Drawings:

Figure 1:

Figure 2 shows the drug release pattern showing the time, specification and results which are achieved through the process of manufacturing of modified release pellets by using drug and polymer matrix solution.

Brief description of the invention:

The description of the invention is mainly described in the following steps without deviating from the actual objective of the present invention.

Preliminarily dissolve the active principle of about nifedipine 5.0 - 6.0 kg, providone of about K-30, 0.75- 1.50 kg and copovidone of about 0.20-0.50 kg in acetone of about 70-90 kg and stir for about 15 minutes to get clear solution (50% acetone)

Accordingly dissolve ethyle cellulose of about 7 - 15 cps in the acetone and mix well.

Add ehtylcellulose solution to drug solution and mix.

Take the sugar spheres into a fluid bed coater (FBC) product bowl and heat the bed to 50°C (45°-55°C)

Set the fluidization with air pressure of 1.5 - 2.5 kg/cm

Then connect the solution tank to FBC bowl through peristaltic pump.

And accordingly load the solution at rate of 7.5 kg/hr (7-8 kg) and ensure pellets are not sticking each other.

Dry the pellets under fluidization.

Accordingly below here is shown the drug release pattern showing the time, specification and results which are achieved through this process of manufacturing of modified release pellets h\ using chug aid polymer matrix solution.

Specification Result

1sthr 10.0-25.0% 17.1

4th hr 25.0-45.0% 38.2

8th hr 40.0-65.0% 56.9

12th hr 55.0-80.0% 71.1

16thhr 65.0-90.0% 82.7

24th hr 75.0-100.0% 98.4

Stability study

Long term condition: 25°C/60%RH

Accelerated condition: 40°C/75%RH

Samples are tested at 3rd and 6th month periods. Long term stability study is under progress.

Table

Plasma concentration study of Nifedipine pellets

These studies on 12 healthy voluntaries shows that plasma peak is observed TM3X at 4th hr, Cmax is 15.1ng/ml and AUC0 is 195.4 and therapeutic effective concentration is maintained for 36hrs.

As per the literature Cmax of Nifedipine with 90mg dosage form is 115ng/ml. Since Nifedipine 8.6% pellets are designed for Nifedipine 30mg capsule and its Minimum therapeutic concentration is 1.9ng/ml. [115/3= 38ng/ml; CMin is 38/20 = 1.9ng/ml; (as per the literature Therapeutic minimum is 20times less than the Therapeutic maximum)] ref: http://wvvw.drugs.com/pro/nj.fediac-cc.htm 1

This study indicates, Nifedipine pellets manufactured in this process are therapeutically effective for about 24hrs

Example 1:

A mixture/solution of _60_ kg is prepared comprising;
45.0-55.0 kg

Step - 1

Active principle: Nifidepine 5.0-6.0 kg

Ethyl cellulose 1.5-3.0 kg

Povidine K-30 0.75-1.50 kg

Copovidone 0.20-0.50 kg

Acetone 70-90 kg

Step 2

Sugar spheres 45.0-55.0 kg

Example 2:

Nifidepine 5.0-6.0 kg

MCCP, HPMC granules 45.0-55.0 kg

Methacrylic acid-Methyl methacrylate co-polymenr 1.5-3.0 kg

Hypromellose (HPMC) 0.75-1.50 k

Copovidone 0.20-0.50 k

IPA 200-300 kg

CLAIMS

1. A method of manufacturing of modified release products by using direct spraying solution technique comprising;

a. Dissolution of active principle along with other excepients in the acetone to form a solution.

b. Heating the sugar spheres in a fluid bed coater product bowl with a suitable temperature.

c. Set the fluidization with suitable air pressure, under controlled inlet and outlet air temperature

d. Connect the solution tank to the fluid bed coater bowl and load the said solution onto sugar spheres at controlled rate of spraying to make the modified released pellets

e. Dry the said pellets under fluidization.

2. A method of manufacturing of modified release products by using direct spraying solution technique according to claim 1, wherein the said optimized active and excipients concentration solution is prepared in suitable solvent.

3. A method of manufacturing of modified release products by using direct spraying solution technique according to claim 1, wherein the said fluid bed coater bowl is heated at a temperature between 45°-55° C.

4. A method of manufacturing of modified release products by using direct spraying solution technique according to claim I, wherein the said air pressure is maintained at 1,5 to 3.0 kg for fluidization

5. A method of manufacturing of modified release products by using direct spraying solution technique according to claim 1, wherein the said air temperature is maintained between 45° C -55° C for inlet and 35° C - 45° C for outlet.

6. A method of manufacturing of modified release products by using direct spraying solution technique according to claim 1, wherein the said solution is loaded on to the sugar spheres at the rate of 7 - 8 kg per hour.