SK111595A3 - Remedial preparation containing morphine sulfate and preparation method thereof - Google Patents

Abstract

The healing preparation contains morphine sulphate having a retardation effect, when talking about the therapy closed to damping of long term strong aches and the medication is releasing of that step by step. This is enabled with the use of different kinds of hydroxypropilmehtyl cellulase which is treated so that, the controlled release is possible. The fundamental steps of the production are based on this principle, that morphine sulphate is mixed with milk sugar, with a mixture of hydroxyproplylene methylcellulase having a different viscosity, when talking about the polymer solution. The dust mixture is coated by water solution of polyvinylpyrolidone. The kernels are pressed based on the granulate and these kernels are coated with the film coating.

Description

The medicinal product contains morphine sulphate with a retarding effect in the treatment of long-lasting severe pain, from which the drug is gradually released. This is made possible by the use of different types of hydroxypropyl methylcellulose in a controlled release formulation. The essence of the production process is to mix morphine sulphate with milk sugar, a mixture of hydroxypropylmethylcelluloses of different viscosities of the polymer solution. An aqueous solution of polyvinylpyrrolidone is applied to the dust mixture. Cores are pressed from the granulate and coated with a film coating.

A medicament containing morphine sulphate and a process for its preparation.

Technical field

The invention is in the field of pharmacy relating to an oral formulation containing morphine sulphate with a retarding effect in the treatment of long-lasting severe pain from which the drug is gradually released.

BACKGROUND OF THE INVENTION

Currently, the world's oral formulations produce a dose of morphine sulphate ranging from 10 to 100 mg, with drug release for 12 to 24 hours. European patent EP 205282 A2 discloses a retard tablet containing morphine sulphate prepared by compression of a granulate coated with cellulose derivatives (hydroxyethylcellulose, hydroxypropylcellulose). The granulate is prepared by mixing the drug into a carrier (cetostearyl alcohol).

European patent EP 377518 A2 describes the preparation of controlled release pellets containing morphine sulphate. One part of the pellets is coated with hydroxypropylmethylcellulose, the other part of the pellets is ethylcellulose and methacrylic acid ester copolymer.

World Patent WO 9422431 A1 describes the preparation of pellets containing morphine salts. The pellets are coated with hydroxypropylmethylcellulose and ethylcellulose.

The disadvantages of the above mentioned methods for producing retard formulations containing morphine sulphate are relatively complicated technology as well as the use of considerable amounts of organic solvents in the individual stages of production.

SUMMARY OF THE INVENTION

The essence of the dosage form according to the invention is that it contains, in addition to sulphate, morphine of the chemical composition {(CnH19NO3) 2.H2SO4.5 H2O} and excipients such as milk sugar, polyvinylpyrrolidone, talc, calcium stearate, other excipients of various types of hydroxypropyl methylcellulose in a controlled release arrangement. The principle of the production process is to mix morphine sulphate with milk sugar, a mixture of hydroxypropylmethylcelluloses of different viscosities of the polymer solution, preferably in a ratio of 1: 1. An aqueous solution of polyvinylpyrrolidone is applied to the dust mixture. Cores are pressed from the granulate and coated with a film coating. The main advantage of the present invention is that the drug preparation process consists of three technologically conventional and uncomplicated processes (granulation, tableting and film coating). The reproducibility of the results is very good. The use of organic solvents is not necessary throughout the entire preparation process, which is important from the point of view of occupational safety and environmental protection. The drug is gradually released from coated tablets in in vitro tests for at least 6 hours.

Various types of hydroxypropyl methylcellulose provide sustained release of the drug - Methocel ^R K100LVCR, Methocel ^R K4MCR, Methocel ^R K15MCR, Methocel ^R K100MCR, Methocel ^R E4MCR, Methocel ^R E10MCR (CR = controlled release). Methocel ^R is a trade mark for semisynthetic cellulose derivatives manufactured by Dow Chemical Co., Midland, Michigan, USA. In a controlled release formulation, these cellulose derivatives are suitable for the preparation of hydrophilic matrix tablets with the desired controlled release of drugs. The characteristics of the individual types of hydroxypropylmethylcellulose are given in the table below:

METHOCEL K.100LVCR K4MCR K15MCR K100MCR E4MCR E10MCR Metoxyl,% 19-24 19-24 19-24 19-24 28-30 28-30 Hydroxypropyl,% 7-12 7-12 7-12 7-12 7-12 7-12 Nominal viscosity 2% aqueous solution at 20 [deg.] C., cP (100 4000 15000 100000 4000 10000 Relative hydration rate the highest lower

Factors that have a decisive influence on drug release control from hydroxypropyl cellulose matrices are: rate of hydration and gel layer formation, viscosity of polymer solution, polymer concentration in matrix, drug solubility, other excipients present (fillers), tablet size and shape, technology used process (direct compression, wet granulation, coating of matrix tablets).

Examples yy / a

The subject matter of the invention is illustrated in the examples without being limited thereto.

Example 1

Kernel composition

Morphine sulphate 0.03000 g

Milk sugar 0,13450 g

Methocel ^R K100LVCR 0.03500 g

Methocel ^R K15MCR 0.03500 g

Polyvinylpyrrolidone 0.00750 g

Talc 0.00500 g

Calcium stearate 0.00300 g

Composition of the film package

Sepifilm 752 White 0.01000 g

Silicone antifoam emulsion 0.00005 g

Polyethylene glycol 0.000125g

Sepifilm 752 White (Seppic Givaudan-Lavirotte, Paris, France) is a granulate containing hydroxypropyl methylcellulose, polyoxyl 40 stearate and titanium dioxide, which is used to coat tablets.

Example 1 - Preparation Method

Morphine sulphate, milk sugar, hydroxypropyl methylcellulose are sieved through a sieve with a mesh side length of 1.5 mm and homogenized. An aqueous solution of polyvinylpyrrolidone is applied to the dust mixture. The wet granulate is dried to a final humidity of 0.5 to 2.0% and the dry granulate is treated through with a mesh side length of 1.25 mm. The granules so treated are homogenized with glidants (talc, calcium stearate) and the cores 9 mm in diameter are pressed to a weight of 0.250 g.

The finished matrix cores are coated on a horizontal or other suitable coating machine at a drying air temperature of 60-70 ° C with an aqueous suspension of Sepifilm 752 White with the addition of a silicone antifoam emulsion. The coated tablets are polished with an aqueous solution of polyethylene glycol.

Example 2

Kernel composition

Morphine sulphate 0.03000 g

Milk sugar 0,13450 g

Methocel ^R K100LVCR 0.0200 g

Methocel ^R K4MCR 0.05000 g

Polyvinylpyrrolidone 0.00750 g

Talc 0.00500 g

Calcium stearate 0.00300 g

Composition of the film package

Sepifilm 752 White 0.01000 g

Silicone antifoam emulsion 0.00005 g

Polyethylene glycol 0.000125g

Example 2 - Preparation Method

The method of preparing the cores and coated tablets is the same as in Example 1.

Example 3

Kernel composition

Morphine sulphate 0.03000 g

Milk sugar 0,15450 g

Methocel ^R K4MCR 0.02500 g

Methocel ^R K15MCR 0.02500 g

Polyvinylpyrrolidone 0.00750 g

Talc 0.00500 g

Calcium stearate 0.00300 g

Composition of the film package

Sepifilm 752 White 0.01000 g

Silicone antifoam emulsion 0.00005 g

Polyethylene glycol 0.000125g

Example 3 - Preparation Method

The method of preparing the cores and coated tablets is the same as in Example 1.

Example 4

Kernel composition

Morphine sulphate 0.03000 g

Milk sugar 0,15450 g

Methocel ^R E4MCR 0.02500 g

Methocel ^R E10MCR 0.02500 g

Polyvinylpyrrolidone 0.00750 g

Talc 0.00500 g

Calcium stearate 0.00300 g

Composition of the film package

Sepifilm 752 White 0.01000 g

Silicone antifoam emulsion 0.00005 g

Polyethylene glycol 0.000125g

Example 4 - Preparation Method

The method of preparing the cores and coated tablets is the same as in Example 1.

The sustained release morphine sulphate has been studied in vitro by the method of a rotating basket 125 rpm ¹ /, dissolution medium - 300 ml of purified water, 37 ° C ± 0.5 ° C warm, intervals of sampling the dissolution medium / after 1, 3, and 6 hours. Analytical determination of morphine sulfate released was performed spectrophotometrically at 285 nm.

The release results from the coated tablets prepared according to each embodiment are shown in the table.

Example # Amount of morphine sulphate released in% time / hour / 1 3 6 1 35.2 67.4 93.3 2 35.4 68.0 94.2 3 23.8 59.3 75.0 4 29.3 58.1 78.8

A medicinal product containing 30 mg of morphine sulphate in retarded form has been clinically tested and compared with a similar product of foreign origin, registered and available in clinical practice.

Clinical follow-up was performed in 24 healthy volunteers. The results obtained (analytical and pharmacokinetic parameters, incidence of adverse reactions) indicate the comparability of the two formulations tested.

Industrial usability

Controlled release coated morphine sulfate tablets can be applied to control long-lasting pain in cancer, as well as pain in severe injuries and burns. When the medicinal product is administered, the side effects of the drug are reduced: respiratory depression, nausea, constipation, vomiting, mental and physical dependence.

PATENT CLAIMS

Claims (1)

A medicament comprising morphine sulfate in an amount of 3.8 to 38 wt. parts and auxiliaries such as milk sugar in an amount of 25 to 75 parts by weight, polyvinylpyrrolidone having a molecular weight of 2 500 to 700 000 in an amount of 0.9 to 5.0 parts by weight, talc in an amount of 0.8 to 2.4 parts by weight Parts, calcium stearate and / or magnesium stearate in an amount of 0.4 to 1.2 wt. . characterized in that it contains hydroxypropylmethylcelluloses with viscosities of polymer solutions of 80 to 100,000 cP, adapted to control the release in a total amount of 10 to 50 wt. parts. A process for the preparation of a medicament according to claim 1, characterized in that morphine sulfate is present in an amount of 3.8 to 38 wt. The mixture is mixed with milk sugar in an amount of 25 to 75 parts by weight and a mixture of hydroxypropyl methylcelluloses having a viscosity of polymer solutions of 80 to 100,000 cP, adapted to control the release in a total amount of 10 to 50% by weight. parts, wherein an aqueous solution of polyvinypyrrolidone having a molecular weight of 2,500 to 700,000 in an amount of 0.9 to 5.0 parts by weight is applied to the dust mixture and cores are pressed from the granulate. Pharmaceutical preparation according to claim 1, characterized _f in that the film-coating comprising hydroxypropyl methylcellulose with a viscosity of the polymer solution of 5 to 25 cP at 0.5 to 3.0 wt.