WO2000066088A1

WO2000066088A1 - Controlled release pharmaceutical preparation containing metamizole

Info

Publication number: WO2000066088A1
Application number: PCT/EP2000/003885
Authority: WO
Inventors: Thomas Strüngmann; Karin Klokkers; Brigitte Freudensprung
Original assignee: Hexal Ag
Priority date: 1999-05-04
Filing date: 2000-04-28
Publication date: 2000-11-09
Also published as: AU4559400A; DE19920415A1

Abstract

The invention relates to a controlled release, solid, orally administered pharmaceutical preparation that contains, as active constituents and embedded in a controlled release matrix, a therapeutically effective quantity of metamizole and/or the salts thereof which are generally recognized as being pharmaceutically safe.

Description

Controlled-release pharmaceuticals containing metamizole

composition

The invention relates to a controlled-release, solid, orally administered pharmaceutical composition which contains a therapeutically effective amount of metamizole and / or its pharmaceutically acceptable salts as active ingredients, embedded in a controlled-release matrix.

Metamizole, N-methyl-N- (2,3-dimethyl-5-oxo-l-phenyl-3-pyrazolin-4-yl) aminomethanesulfonic acid, is an antipyretic analgesic. The analgesic effect is achieved by damping the central pain perception as a result of activation of neurons in the pain-relieving system. The lowering of the increased body temperature is mediated by the attack on the hypothalamic heat regulation center, as a result of which an increased heat release via the periphery occurs. After oral administration, the absorption of metamizole is preceded by hydrolysis to 4-methylaminoantipyrine in the liver. 4-Methylaminoantipyrin and the resulting 4-aminoantipyrine are the pharmacologically active metabolites of metamizole, while the other metabolites 4-acetylaminoantipyrine (main metabolite in urine) and 4-formylaminoantipyrine are considered to be much less pharmacologically active or inactive.

The dosage forms previously on the market are only quick-release. They are used to treat severe acute and chronic pain as well as fever. Although the therapy with fast-releasing active substances tries to maintain a sustained therapeutically effective blood plasma level of the active substance by frequent and at the same time taking the active substance, large fluctuations in the blood plasma level occur due to the immediate absorption, the systemic excretion and the hepatic metabolism of the active substance. This can severely impair the effectiveness of the active ingredient. After the oral intake of a rapidly releasing pharmaceutical composition, a very high blood plasma level of the active ingredient is reached for a short time. The blood plasma level drops shortly after ingestion and a sufficient therapeutic effect can no longer be guaranteed. Since, as mentioned above, metamizole is used not only for the treatment of acute but often also for chronic pain, an optimal and constant effect over a longer period of time cannot be guaranteed when taking the previously known rapid-release pharmaceutical compositions.

The object of the present invention is to provide a pharmaceutical composition containing metamizole and / or its pharmaceutically acceptable salts, which ensures a therapeutically effective, constant blood plasma level over a period of at least 8 hours.

The object is achieved according to the invention by a pharmaceutical composition containing metamizole and / or its pharmaceutically acceptable salts, which has a solid consistency, is to be administered orally, releases the active substance in a matrix-controlled manner and over a period of at least 8 to 12 hours, optionally up to 24 hours ensures a therapeutically effective blood plasma level. By avoiding the fluctuations in the blood plasma level with respect to the active ingredient, an optimal effectiveness against the pain can be achieved with minimal side effects. In addition, patient compliance is improved by the reduced frequency of ingestion. Since metamizole is very water-soluble, it was not to be expected that a matrix-controlled slow release formulation would guarantee a satisfactory, delayed release. Particularly suitable pharmaceutically acceptable salts of metamizole are alkali metal salts, such as the potassium, sodium and lithium salts, in particular the metamizole sodium monohydrate, and the ammonium salt.

The composition according to the invention contains an analgesically effective amount of metamizole and / or its pharmaceutically acceptable salts of 500-2500 mg per dosage unit.

An amount of metamizole sodium monohydrate per dosage unit of 500-2000 mg, in particular 500 mg, 1000 mg and 1500 mg metamizole sodium monohydrate per dosage unit is preferred.

The composition according to the invention can be in the form of granules, pellets, spheroids. These can either be filled into capsules or sachets or pressed into tablets or tabs. If necessary, the active ingredient and possible excipients can also be tabletted directly.

The tabs or sachets are dispersed in water before ingestion, i.e. after the addition of the tabs or sachet to water, the retarded particles are finely dispersed in the water and can be drunk by the patient, the retarding effect being retained and the ingestion is made easier for the patient since there are no difficulty swallowing.

The active ingredient metamizole and / or its pharmaceutically acceptable salts used in the composition according to the invention can be embedded in a matrix. This matrix ensures the controlled release of metamizole and / or its pharmaceutically acceptable salts over a period of at least 8 to 12 hours and possibly up to 24 hours (matrix-controlled).

Suitable matrix-forming materials:

Hydrophilic or hydrophobic polymers, e.g. Starch, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose,

Hydroxymethyl cellulose, poly (vinyl alcohols), alginates, polydextrose, carboxymethylene, hydrogenated hydroxyalkyl cellulose, hydroxypropyl methyl cellulose ether, polyvinyl chloride, Ethyl cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetates,

Cellulose acetate phthalates, ethylene vinyl alcohol, alginic acid and / or their derivatives, acrylic acid and / or methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylates, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkyl polyamide methyl methacrylate), poly (methacrylic anhydride), methyl methacrylate,

Polymethacrylates, poly (methyl methacrylate) copolymer, polyacrylamides,

Aminoalkyl methacrylate copolymers and / or glycidyl methacrylate copolymers. Methylcellulose, polyvinylpyrrolidone and / or alginic acid and / or their salts and / or derivatives are preferably used as matrix formers in the composition according to the invention. The composition according to the invention contains 1-90% (weight percent) of one or more of the hydrophilic or hydrophobic polymers as a matrix.

The preferred matrix form according to the invention can the active ingredient metamizole and / or its pharmaceutically acceptable salts in a gel-forming matrix from e.g.

Methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,

Hydroxypropylmethylcellulose, alginate and / or polyacrylic acid, in particular

Methyl cellulose, embedded, included. The polymer hydrates and forms a gel-like

Layer that slowly erodes and thus releases the active ingredient in a controlled manner. According to the prior art, 30-35% by weight of retardant, based on the delayed-release component of the overall formulation, is used in a gel-forming matrix if a readily water-soluble active ingredient is to be released as an active ingredient with a delay. In contrast, the composition according to the invention contains 5-25% by weight, in particular 10-25

% By weight of retardant based on the delayed-release component of the overall formulation, sufficient delayed release being ensured.

In addition to the active ingredient metamizole and / or its pharmaceutically acceptable salts, a further matrix form according to the invention can contain known water-soluble auxiliary substances which, like the active substance, are embedded in a framework formed from water-insoluble, indigestible auxiliary substances. By removing the soluble components, pores are created through which the active ingredient diffuses outwards. Polymers such as polyvinyl chloride, polyethylene, polyamide, silicone, ethyl cellulose and methacrylic acrylate copolymers can be used as scaffolding substances. The active ingredient Auxiliary mixture is pressed either directly or after wet granulation with organic solvents or binder solutions into tablets or tabs or filled in capsule or sachet in pellet form.

Other pharmaceutically acceptable excipients which are common in the art, e.g. Diluents, lubricants, binders, granulation aids, colorants, flavors, detergents, buffers, non-stick agents and lubricants can also be contained in the controlled release matrix.

The composition according to the invention embedded in a controlled-release matrix can also be film-coated with a known, pharmaceutically suitable, non-controlled-release coating agent, an aqueous film coating being preferred.

The release rate of the sustained release composition according to the invention is 5-50% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after one hour, 10-75% (weight percent)

Metamizole and / or the corresponding pharmaceutically acceptable salts after two

Hours, 20-95% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after four hours, 40-100% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after eight

Hours, more than 50% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after twelve hours, more than 70% (weight percent)

Metamizole and / or the corresponding pharmaceutically acceptable salts after eighteen

Hours and more than 80% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after twenty-four hours. Figure 1 shows the

Release of the composition according to the invention in water over a period of

500 minutes.

Furthermore, in the delayed-release composition according to the invention, at least 70-95% (weight percent) of metamizole and / or the corresponding pharmaceutically acceptable salts is obtained after eight hours, and at least 77-97 after ten hours

% (Weight percent) metamizole and / or the corresponding pharmaceutical harmless salts and after twelve hours at least 80-100% metamizole and / or the corresponding pharmaceutically acceptable salts in vivo.

Another embodiment of the invention can consist of an initial dose (ID) and a delayed release component. The initial dose contains metamizole and / or its pharmaceutically acceptable salts as powder, granules and / or pellets, each in addition to optional adjuvants. The metamizole and / or its pharmaceutically acceptable salts contained in the initial dose is released immediately after ingestion. The therapeutically effective blood plasma level is reached very quickly by means of this initial dose, so that a therapeutic effect can be seen shortly after ingestion. The delayed-release component contains metamizole and / or its pharmaceutically acceptable salts as granules and / or pellets, each in addition to optional auxiliaries. This delayed release component is responsible for maintaining the therapeutically effective blood plasma level for several hours. The patient can thus be guaranteed a consistently high blood plasma level for several hours. The granules or the pellets can contain retarding auxiliaries which form a controlled release matrix. The matrix formers mentioned above can be used as suitable substances which form a controlled release matrix. The above-mentioned information regarding the amount of retardant and active ingredient content also apply to the ID formulation.

In the initial dose, the content of metamizole and / or its pharmaceutically acceptable salts can be 5-50% by weight of the total active substance content. The ratio of active substance content in the initial dose to active substance content in the delayed-release component can be 1: 1 to 1: 5. A ratio of 1: 1, 1: 2, 1: 3 or 1: 4 is preferred.

The composition according to the invention can be in the form of sachets, the sachet containing the initial dose and the retarding component, as described above. The initial dose can be in the form of powder, granules and / or pellets. The retarding component can be present as granules and / or pellets. The sachet content is dissolved in water before ingestion so that the initial dose is in solution and the retarded particles are finely dispersed in the solution. The preparation according to the invention can be in the form of tabs, the initial dose being pressed with the retarding component. The initial dose can be pressed in the form of powder, granules and / or pellets. The retarding component can be pressed in the form of granules and / or pellets. The tabs are dissolved in water before ingestion so that the initial dose is in solution and the retarded particles are finely dispersed in the solution.

The preparation according to the invention can be in the form of a two-layer tablet. The first layer represents the initial dose which is pressed from powder and optionally auxiliary substances, the granulate and / or pellets described above. The second layer contains the delayed-release component described above, which is pressed from the corresponding granules and / or pellets.

The release rate of the sustained release composition according to the invention with the initial dose (ID formulation) in vitro is 15-30% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after 30 minutes, 30-60% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after three hours and more than 70% (weight percent) metamizole and / or the corresponding pharmaceutically acceptable salts after eight hours.

The pharmaceutical auxiliaries known in the prior art, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, retardants and / or antioxidants, and / or other known carriers and / or Thinners are used.

The invention is explained in more detail by the following examples, but without thereby restricting the scope of the invention. Example 1:

Metamizole sodium 1 H ₂ O, methyl cellulose and lactose are mixed and passed through a sieve. This mixture is then moistened with a solution of PVP and water. Then it is granulated in a fluidized bed granulator. The granules are mixed with microcrystalline cellulose, magnesium stearate and Aerosil and compressed into tablets.

Example 2;

Metamizole sodium 1 H ₂ O, methyl cellulose and lactose are mixed and passed through a sieve. This mixture is then moistened with a solution of PVP and water. Then it is granulated in a fluidized bed granulator. The granulate comes with microcrystalline cellulose, magnesium stearate and Aerosil mixed and compressed into tablets.

Example 3:

Metamizole sodium 1 H ₂ O, methyl cellulose and lactose are mixed and passed through a sieve. This mixture is then moistened with a solution of PVP and water. Then it is granulated in a fluidized bed granulator. The granulate is mixed with magnesium stearate and Aerosil and filled into sachets.

Example 4;

The following substances are used to produce 1000 tablets [1350 mg total weight, 500 mg metamizole sodium 1 H ₂ O].

Metamizole sodium 1 H ₂ O, mannitol, lactose, hydroxyethyl cellulose and hydroxypropyl cellulose (15 g as a binder) are mixed dry. The mixture is then moistened with water until a moist granulating compound is obtained. The moistened mixture is then lightly dried in a Fluid Bed Dryer (FBD) at 60 ° C., granulated and sieved through a sieve with a mesh size of 12. The granules are then completely dried in an FBD at 60 ° C., regranulated and sieved through a 1.25 mm sieve (mesh size 16). Molten cetylstearyl alcohol is added to the warm metamizole sodium 1 H ₂ O granules and mixed. The mixture is cooled in an air stream, regranulated and sieved through a 1.25 mm sieve. The remaining hydroxypropyl cellulose (10 g) is added to the mixture and mixed with the granules until the granules have a sufficiently thick coating of hydroxypropyl cellulose. The granules are then pressed into tablets. If necessary, the tablets can still be coated with standard coatings.

Example 5:

Dioctyl sodium sulphosuccinate is dissolved in isopropanol. Carboxymethyl cellulose is mixed with this solution until the mixture is homogeneous. The mixture is then granulated and sieved through a 16 mesh screen. The granules are dried in an air stream until all of the isopropanol has evaporated. Metamizole sodium 1 H ₂ O and lactose are added and mixed. Magnesium stearate and talc are then added and mixed until a homogeneous mixture is obtained. Following is the mixture was regranulated and sieved through a 16 mesh screen. The granules obtained are pressed into tablets or filled into sachets. The amount per tablet or sachet of metamizole sodium 1 H ₂ O is 1000 mg. 1000 pieces are made, each with a total weight of 1513mg.

Example 6:

Metamizole sodium 1 H ₂ O and polyvinyl pyrrolidone (PVP) are mixed rapidly in an appropriate apparatus. Eudragit is dissolved in acetone / isopropanol (50:50) (granulation fluid). This granulation fluid is then slowly added during the mixing process of metamizole sodium 1 H ₂ O and PVP until a moist granulation mass is formed. The resulting granulate is then dried and sieved through a sieve with a mesh size of 12. The cetostearyl alcohol melted at a temperature of 60-70 ° C is added to the still warm granulate and mixed. After cooling, the granules are sieved through a 1.7 mm sieve. Then the talc and magnesium stearate are added and mixed in. The granules are either compressed into tablets or filled into sachets.

Example 7:

500 g of metamizole sodium 1 H ₂ O is mixed with 40 g of ethyl cellulose and 25 g of polyvinylpyrrolidone. Then 140 g lactose and 203 g talc are added, moistened with a sufficient amount of alcohol and granulated and then dried. The granules obtained are either compressed into tablets or filled into capsules. A dose unit produced in this way contains 500 mg of metamizole sodium 1 H ₂ O.

Example 8:

Two-layer tablet: Initial dose:

Retarded dose:

Production of the slow release granules:

Kollidon is dissolved in water and the green paint is dispersed in it. Metamizole sodium 1 H ₂ O, lactose and metolose are placed in a fluidized bed granulator and granulated with the previously prepared solution. Magnesium stearate is added to the granules obtained and Aerosil added and passed through a 1.0 mm forced sieve and homogenized in the container mixer.

Preparation of the initial dose:

The entire ingredients of the initial dose are passed through a 0.8 mm forced sieve and homogenized in the container mixer.

The prolonged-release granules are compressed with the initial dose on a suitable rotary tablet machine to form two-layer tablets.

Example 9:

ID sachet:

The following two components are provided for the metamizole sodium 1 H ₂ O ID sachet.

Component 1 dnitial dose):

Metamizole sodium 1 H ₂ O 500.00mg

Microcrystalline cellulose 40.00mg

Component 2 (sustained release dose):

Metamizole sodium 1 H ₂ O 1000.00mg

Microcrystalline cellulose 81, 60 mg

Opadry, white, consisting of lactose H ₂ O 5.50 mg

Hydroxypropyl methyl cellulose 6.25 mg

Titanium dioxide 2.45 mg

Macrogol 4000 1.50 mg

Eudragit S 100 150.00 mg

Dibutyl phthalate 5.00 mg These two types of granules or pellets, which were produced from components 1 and 2, are filled into sachets. The active substance concentration of metamizole sodium 1 H ₂ O per sachet is 1500 mg.

Example 10:

ID tab:

The following two components are provided for the metamizole sodium 1 H ₂ O -ID tab.

Component 1 (initial dose powder):

Metamizole sodium 1 H ₂ O 500.00mg

Component 2 (sustained release dose):

Metamizole sodium 1 H ₂ O 1000.00mg

Microcrystalline cellulose 130.00 mg

Lactose 100.00 mg

Methyl cellulose 200.00 mg

Polyvinylpyrrolidone 50.00 mg

Magnesium stearate 20.00 mg

The sustained release granules or the sustained release pellets, which were produced from component 2, are pressed with component 1 into a tab. The active substance concentration of metamizole sodium 1 H ₂ O per sachet is 1500 mg.

Example 11:

ID tab:

Component 1 (initial dose Garnulaf):

Metamizole sodium 1 H ₂ O 500.00 mg microcrystalline cellulose 50.00 mg

Component 2 (sustained release dose):

Metamizole sodium 1 H ₂ O 1500.00 mg

Microcrystalline cellulose 130.00 mg

Lactose 100.00 mg

Methyl cellulose 200.00 mg

Polyvinylpyrrolidone 50.00 mg

Magnesium stearate 20.00 mg

These two types of granules or pellets, which were produced from components 1 or 2, are mixed and pressed into a tab. The active substance concentration of metamizole sodium 1 H ₂ O per sachet is 2000 mg.

Example 12:

This tablet core can also be covered with a film.

Example 13:

Ingredients weight ürmg tabs _'

Metamizole sodium 1 H ₂ O 1000

Methyl cellulose 200

Lactose 200

Polyvinyl pyrrolidone 50

Magnesium stearate 20

Aerosil 4

Metamizole sodium 1 H ₂ O, methyl cellulose and lactose are mixed and passed through a sieve. This mixture is then moistened with a solution of PVP and water. Then it is granulated in a fluidized bed granulator. The granules are mixed with magnesium stearate and Aerosil and pressed into tabs.

Claims

claims

1. Pharmaceutical composition with controlled release, characterized by the embedding of a therapeutically effective amount of metamizole and / or its pharmaceutically acceptable salts as active components in a matrix which controls the controlled release.

2. Pharmaceutical composition with controlled release according to claim 1, characterized by alkali salts and / or ammonium salts of metamizole, in particular metamizole sodium monohydrate, as active ingredients.

3. Pharmaceutical composition with controlled release according to claim 1 or 2, characterized by 500-2500 mg metamizole and / or its pharmaceutically acceptable salts per dosage unit.

4. Pharmaceutical composition with controlled release according to claim 3, characterized by 500-2000 mg, in particular 500 mg, 1000 mg or 1500 mg, metamizole sodium monohydrate per dosage unit.

5. Pharmaceutical composition with controlled release according to one of the preceding claims, characterized by a controlled release matrix, the hydrophilic and / or hydrophobic polymers, in particular starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,

Hydroxyethyl cellulose, hydroxymethyl cellulose, poly (vinyl alcohols), alginates, polydextrose, carboxymethylene, hydrogenated hydroxyalkyl cellulose, Hydroxypropyl methyl cellulose ether, polyvinyl chloride, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetates, cellulose acetate phthalates,

Ethylene vinyl alcohol, alginic acid and / or its derivatives, acrylic acid and / or methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylates, aminoalkyl methacrylate copolymers,

Poly (acrylic acid), poly (methacrylic acid), methacrylic acid-alkylamide copolymers, poly (methyl methacrylate), poly (methacrylic acid anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide,

Contains aminoalkyl methacrylate copolymers and / or glycidyl methacrylate copolymers as a retardant.

6. A controlled release pharmaceutical composition according to claim 5, characterized by a gel-forming matrix containing methyl cellulose as a retardant

7. A pharmaceutical composition with controlled release according to claim 5 or 6, characterized by a content of the retardant based on the delayed release component of the total formulation of 1-90 wt.%, In particular 5-25 wt.%.

8. Pharmaceutical composition with controlled release according to claim 5, 6 or 7, characterized by a content of gel-forming methyl cellulose as a retardant based on the delayed release component of the

Total formulation of 10-25% by weight.

9. A controlled release pharmaceutical composition according to any one of the preceding claims in the form of granules, pellets, spheroids, which can be filled into capsules or sachets or compressed into tablets or tabs.

10. A controlled release pharmaceutical composition according to any one of the preceding claims, which comprises or consists of the following components: i) an initial drug dose (ID) containing a therapeutically effective amount of metamizole and / or its pharmaceutically acceptable salts as active ingredients in addition to optional adjuvants contains. ii) a sustained release component, which has a therapeutically effective amount of metamizole and / or its pharmaceutically acceptable salts as active Contains components embedded in a delayed release matrix in addition to optional auxiliaries.

11. The pharmaceutical composition with controlled release according to claim 10, characterized by a ratio of active substance content in the initial dose to active substance content in the delayed-release component of 1: 1 to 1: 5, in particular of 1: 1, 1: 2, 1: 3, 1: 4.

12. A controlled release pharmaceutical composition according to claim 10 or 11 in the form of a sachet, the sachet containing the loading dose and the sustained release component.

13. A controlled release pharmaceutical composition according to claim 10 or 11 in the form of tabs, the tab containing the loading dose and the sustained release component.

14. A controlled release pharmaceutical composition according to claim 10 or 11 in the form of a two-layer tablet, the first layer consisting of the initial dose and the second layer consisting of the sustained release component.

15. Pharmaceutical composition with controlled release according to one of the preceding claims, characterized by tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, lubricants, plasticizers, wetting agents, dispersants, emulsifiers, retardants, binders, granulation aids, colorants, flavorings, detergents, buffers, non-stick agents,

Lubricants, antioxidants, and / or other known carriers and diluents as auxiliaries.