The method of obtaining enteric preparation containing interferon-alpha and enteral preparation containing interferon-alpha in the form of tablets

 

(57) Abstract:

The invention relates to pharmaceutical industry and relates to obtaining tablets containing interferon-alpha and intended for enteral application. The invention consists in that upon receipt of the tablets use of freeze-dried human genetically engineered alpha-2-interferon with the content 1105- 1106IU, as filler add sterile lactose, as a binder, providing flowability, stabilizer and to give a taste - sterile calcium stearate and sucrose. At the core of the tablet, suspended in the air stream sprayed coating from a solution of cellulose acetate and castor oil mixed with acetone and alcohol. 2 C. p. F.-ly, 4 PL.

The invention relates to pharmaceutical industry and relates to obtaining tablets containing alpha-interferon (IFN) for enteral application.

Currently, the following dosage form of interferon: injection solutions, lyophilized form, liposomes, rectal and vaginal legform, ointments, aerosols, eye drops and films, and oral solutions.

gene" in cooperation with the firm "sharing Plat" is available in injectable lyophilized preparation of genetically engineered alpha-2 IFN commercial name "intron". FDA-USA recommends that "intron a for subcutaneous and intramuscular injection.

The Swiss company Hoffmann-La Roche, which produces genetically engineered alpha-2 IFN "he" gave license to his production company "Interferon Sciences, Inc." After its official approval to the FDA, the U.S. drug received the trade name "Interferon II injection".

It should be noted as the closest to the proposed message on the development of oral dosage form of interferon, non-toxic, easily absorbed in the gastrointestinal tract. Active ingredients: 5 to 100 mm of unsaturated fatty acids (linoleic, linolenic, oleic, and others), 0,2 4 esters and polyoxyethylene fatty acid esters of alkylpolyoxyethylene or other surfactant; about 1107IU IFN and water. Thus prepared oral legform IFN increases its resistance to the action of the enzyme, it achieves its high concentration in the blood.

Unlike injectable interferon, which can cause undesirable consequences in the form of a syringe infections, offer oral tablet form of human recombinant alpha-2 interferon suited better for clinical use, easy Transline solutions IFN also inferior tabletirovaniem forms, since the latter with acid-resistant coatings can be used for enteral application, so as to protect the active principle from the intact impact of gastric contents. In addition, the tablets are strictly dosed in the application and is more efficient because it does not require special packaging.

Offer tableted form of human recombinant genetically engineered alpha-2 IFN contains 11051106IU lyophilized IFN. As the main filler use sterile lactose, as a binder, providing flowability tablets, stabilizer and impart flavor, use sterile calcium stearate and sucrose. Generated from these components the core tablets suspended in the air stream, spray-applied coating from a solution of acetylcellulose (AFC) and castor oil in a mixture of acetone and alcohol.

It is known that in the process of obtaining tablets of the biological activity of IFN is destroyed. In the manufacture of tablets from a liquid IFN with lactose no added stabilizers activity of IFN was reduced 16-fold, with stabilizing substances 2-4 times (Wi pigs with 10% sugar; 5% alabalaba (lipid extract of the microalga Chlorella) with 5% donor bovine serum albumin and 10% sugar.

In the manufacture of tablets from a mixture of dry (lyophilized) IFN with lactose loss of activity was almost the same as when using liquid IFN with a stabilizer, i.e., the reduction of 4 times.

The activity of IFN in tablets obtained from a source of dry or liquid IFN, see table. 2.

The same level of reduction of the activity found in tablets made of different quantities of dry IFN from 5105IU up to 1,5107on the tablet (PL.3).

Thus, in the manufacture of tablets from a liquid IFN require the use of additional stabilizers to reduce loss of activity, in particular 5% donor bovine serum albumin with 10% sugar. In the manufacture of tablets from dry IFN there is no need of any stabilizers.

For tabletirovannyh forms previously was justified and used filler consisting of starch, glucose, sucrose, lactose, cocoa (MRTU 42-396-71). At reception of tablets pre-prepared granulate, which is then mixed with the active beginning, vanillin, calcium stearate and tabletservice. Developed the I technological process of production of tablets of the composition of the filler were excluded non-standard and inseminated by other organisms (starch, cocoa) or hygroscopic (glucose) components. It is possible to avoid pre-granulation and reduce humidity tablets up to 3

Thus, to obtain tabletirovannoj forms of human recombinant genetically engineered alpha-2 IFN was used, the filler consisting of the following components:

lactose 72-79

sucrose 9-16

calcium stearate 2

All these substances permitted for use in tabletirovannoj form.

As a protective enteric-soluble coating in the domestic chemical-pharmaceutical industry are mainly used film-based AFC or shellac.

For coating AFC and castor oil are dissolved in a mixture of acetone and alcohol, shellac dissolved in water. In the first case, the coating is applied in the most gentle conditions (temperature 18-20oC, duration 20-30 min). For enteral forms of alpha-2 interferon is recommended to use a coating of AFC and castor oil.

Example 1. Obtaining tablets containing human recombinant genetically engineered alpha-2 interferon in the amount of 1106IU.

The composition contains: 80 g lactose, sucrose 18 g calcium stearate 2 g liofilizirovannami activity 5108IU (per tablet 1106IU).

The composition is formed into a pill mass of 0.2 g

Tablets prepared as follows. Sterile lactose, sucrose and calcium stearate are mixed, add the powder IFN and again mix thoroughly. Tablets are pressed into teletrauma car (get about 450 tablets 0,2 g, given the waste mass). Then apply a protective coating. Prepare 10% solution AFC in a mixture of acetone with ethanol in a volume ratio of 3:2 and add castor oil to a content of 0.2 in the mixture (for example, 90 g of castor oil, 450 g AFC, 3,384 kg of ethyl alcohol and 5,076 kg of acetone).

Example 2. Obtaining tablets containing human recombinant genetically engineered alpha-2 interferon in the amount of 1105IU.

The tabletting mixture is prepared analogously to example 1, except for the estimated activity of IFN in the tablet (1105IU) total specific activity should be 5,5108IU.

Thus, the following technology for enteral forms of human recombinant genetically engineered alpha-2 interferon: a source of biologically active material was mixed with napolnitel shell of AFC (see table.4).

1. The method of obtaining enteric preparation containing interferon-alpha, wherein preparing a tablet-based human recombinant genetically engineered alpha-2 interferon pressing powdered ingredients and then cover shell comprising acetylcellulose.

2. Enteral preparation containing interferon-alpha in the form of tablets, including human recombinant genetically engineered alpha-2 interferon, lactose, sucrose, calcium stearate, acetylcellulose, castor oil in the following ratio:

Human recombinant genetically engineered alpha-2 interferon, IU 1 1051 106< / BR>
as well as, wt.

Lactose 72 79

Sucrose 9 16

Calcium stearate 2

Acetylcellulose 8

Castor oil 20

 

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3 ex, 1 tbl

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