WO2015027303A1

WO2015027303A1 - Method for manufacturing a pharmaceutical combination containing an analgesic agent and an antispasmodic agent and pharmaceutical combination

Info

Publication number: WO2015027303A1
Application number: PCT/BR2014/000214
Authority: WO
Inventors: Jaime ABRAMOWICZ; Fernando Rafael De Souza; Carlos Antonio Martins
Original assignee: Diffucap Chemobras Quimica E Farmaceutica Ltda
Priority date: 2013-08-28
Filing date: 2014-06-30
Publication date: 2015-03-05

Abstract

Method for manufacturing a pharmaceutical combination containing an analgesic agent and an antispasmodic agent and pharmaceutical combination relates to a method for manufacturing a novel pharmaceutical combination containing an analgesic agent, Ketorolac tromethamine, and an antispasmodic agent, such as Hyoscine or Pargeverine; each of these active agents is manufactured in the form of microgranules, those related to Ketorolac being immediate release microgranules and those related to Hyoscine or Pargeverine being controlled release microgranules, coating polymers being added to the latter to obtain the appropriate release profile; the microgranules are incorporated in a capsule in different proportions; said method comprises the following steps: 1): Manufacturing the immediate release microgranules of the Ketorolac tromethamine analgesic by means of a total of ten substeps; 2) Manufacturing the controlled release microgranules of the Hyoscine or Pargeverine antispasmodic agent by means of a total of ten substeps; the composition of the contents of each capsule containing immediate release microgranules of the Ketorolac tromethamine analgesic and controlled release microgranules of the Hyoscine or Pargeverine antispasmodic agent is as follows: Ketorolac tromethamine: 2.5%-15% by weight, Hyoscine or Pargeverine: 2.5%-15% by weight, Povidone (PVP K30): 1%-5% by weight, white talcum: 5%-30% by weight, dyes (yellow + green): 0.03%-0.06% by weight, core (sugar and starch): 87.97%-29.94% by weight, coating polymers: 1%-5% by weight.

Description

"PROCEDURE FOR MANUFACTURING A PHARMACEUTICAL COMBINATION CONTAINING ANALGESIC AGENT AND ANTIESPASMODIC AGENT AND PHARMACEUTICAL COMBINATION"

APPLICATION FIELD

The present patent application has as its main object a manufacturing procedure for a new pharmaceutical combination and the obtained pharmaceutical combination, composed of an analgesic, Tromethamine Ketorolac (5-Benzoyl-2,3-dihydro-1H-pyrrolysin-1 1-earboxylic acid, 2-amino-2-hydroxymethyl-1,3-propanediol), in antiospasmodic type of Hioscin or Pargeverine.

More specifically, the present application relates to a new pharmaceutical combination procedure of the specified type, which has been designed and developed as a result of experience in dosing the Tromethamine Ketorolac analgesic and a Hioscin or Pargeverine antispasmodic . Thus, the procedure of the present patent application allows to obtain microgranules of each active ingredient separately in order to avoid contact incompatibility between the analgesic agent and the antispasmodic agent, which form the new invention obtained by the procedure described and claimed. in the present invention patent application.

Etor Tromethamine Ketorolac is a non-steroidal anti-inflammatory with analgesic, anti-inflammatory and antipyretic action, whose mechanism of action It is related to its ability to inhibit prostaglandin synthesis and a peripheral analgesic effect.

Hyoscine is an alkaloid synthesized by certain plants that produces an anticholinergic effect exerting an antispasmodic action on the smooth muscle of the gastrointestinal, biliary and genitourinary tract. Â Pargeverine is a moderate and non-selective antispasmodic antagonist of muscarinic receptors that acts directly on visceral smooth muscle, ie, it inhibits the activity of muscarinic receptors located mostly in the smooth muscle of some organs and glands.

TECHNICAL STATE

Ketorolac has been known since 1978 from Belgian Patent Nos. 856,681 and U.S. Patent No. 4,089,969, which are mentioned as prior art to the present inventive development in the field of pharmacology.

. Both patents belong to Syntex and define Ketorolac in its preparation and its anti-inflammatory and analgesic action. Ketorolac is a prostaglandin synthesis inhibitor with peripheral analgesic effect, of which no effect on opioid receptors has been demonstrated.

It is rapidly absorbed soon after oral and intramuscular administration, with a peak plasma concentration between 1 and 2 hours and its average life ranging between 4 and 8 hours. 99% of Cetorolaco joins the plasma proteins and if administered every 6 hours the peak plasma concentration will be reached within 24 hours, then a loading dose may be required to reduce the time to achieve a relevant analgesic effect. The main route of elimination of Ketorolac and its metabolites (parahydroxylated and conjugated) is the urinary (92%), eliminating the remainder through feces. The usual daily dose ranges from 40mg to 80mg, administered through various daily intakes and the maximum dose being 90mg / day.

The chemical formula of hyoscine (C17H21NO4) differs from atropine only in that it has an oxygen bridge between carbon atoms 6 and 7, which gives it the possibility of penetration into the blood-brain barrier, although the N-Butylbromuro derivative used in this patent application. of invention do not cross it.

Pargeverine has a dual effect on the smooth muscle of the hollow viscera. On the one hand, the most important is its potent musculotropic effect, 96 times greater than that of Papaverine (the head drug of the musculotropic antispasmodic group), which is probably due to a blockage of calcium intake from the muscle cell. On the other hand, it exerts a mild neurotropic (anticholinergic) action by competing with acetylcholine for its muscarinic receptor, but with 17 times less potency than atropine. In this way Pargeverine quickly nullifies the painful spasm and allows the smooth muscle to regain its normal tone.

In the market are known antispasmodic and analgesic combinations for the treatment of gastrointestinal, biliary tract and genitourinary tract pain. These preparations combine the action of an antispasmodic with various analgesics such as Paracetamol, Dipyrone and Ibuprofen, with no background referring to a combination of an antispasmodic with Tromethamine Ketorolac as an analgesic agent.

It has been shown that there is an important interaction between analgesics and antispasmodics in these preparations, which causes a high degree of neutralization of the effects of the active principles, ranging from 40% to 90%, leading to the consequent decrease in their plasma concentrations.

According to existing literature, the most important interaction between Tromethamine Ketorolac and an antispasmodic is found in combination with Hyoscine, which is why the present patent application describes a manufacturing procedure for a new pharmaceutical combination that was designed in a preferred embodiment, in different microgranules separated for each active principle, avoiding their contact and interaction in the manufacture, conservation and packaging, and also in vivo, once ingested by the patient.

OBJECT OF THE INVENTION

For the purposes specified, the subject-matter of this application relates to a manufacturing procedure for a novel pharmaceutical combination and the pharmaceutical combination obtained which comprises in its formulation immediate release microgranules containing the analgesic Tretoramine Ketorolac (5-Benzoyl-2,3-dihydro-1H-pyrrolysin-1-carboxylic acid , 2-amino-2-hydroxymethyl-1,3-propanediol), and scheduled release microgranules containing an antispasmodic agent such as hyoscine or pargeverine.

The composition of this new combination has been designed to avoid the interaction of the active ingredients both during manufacture and in vivo once ingested by the patient.

This is achieved with the procedure of the present patent application, whereby microgranules containing each active ingredient are manufactured. The microgranules containing the active ingredient Ketorolac of Tromethamine are designed to be immediate release, being made with nuclei composed of sugar and starch, to which the micronized active principle is incorporated by means of binder polymers. Thus, high plasma analgesic concentrations are rapidly achieved.

The microgranules containing the antispasmodic active ingredient Hioscin or Pargeverine are designed to be of. scheduled release, to which coating polymers are added to them to achieve the appropriate release profile. In this way the gradual release in the organism is achieved, in times and different areas of the analgesic.

DESCRIPTION

In order to make the object of the present patent application more intelligible, the following is a demonstrative example of how it can be put into practice, with the express clarification that precisely because it is an example, It cannot be attributed to it as limiting the scope of the protection of the present patent application, but simply as a purely illustrative intention of the basic conception of its grounds.

Example

The manufacturing procedure for a batch of 46,000 doses of each active agent comprises the following steps:

Step 1): Manufacture of the immediate release microgranules of the Tromethamine Ketorolac analgesic comprising the following substeps:

1.1) Dissolve in a suitable vessel under strong agitation from 2.130 g to 2.890 g, preferably 2.512 g of tartrazine yellow dye, and from 0.020 Kg to 0.030 Kg, preferably 0.025 Kg of purified water.

1.2) Add after dissolution of the dye under stirring from 0.009 Kg to 0.015 Kg, preferably 0.012 Kg of isopropyl alcohol.

1.3) Place in a container of suitable capacity from 0,400 kg to 0,600 kg, preferably 0,500 kg of talc and add the dye obtained in 1.2) by stirring until the mixture is homogenized.

) Dry the mixture obtained in 1.2) by drying the heat of a greenhouse at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours. The weight of this talc and dye mixture will be from 0.400 kg to 0.600 kg, preferably 0.502 kg.

) Mix from 0.300 Kg to 0.700 Kg, preferably 0.500 Kg of 50% by weight Tromethamine Ketorolac (preferably 0.251 Kg) of yellow talc obtained in 1.4) previously sieved in 0.600 mm mesh for the purpose of eliminating the grains.

) Prepare a 10% solution of Povidone (PVP K30) in a suitable container by dissolving with stirring until a clear solution of 0.080 kg to 0.120 kg, preferably 0.100 kg of Povidone (PVP K30) with 0.700 to 1.200 kg preferably 0.900 kg of isopropyl alcohol to obtain from 0.780 kg to 1.320 kg, preferably 1,000 kg of 10% Povidone (PVP K30) solution.

) Place in a suitable capacity stainless steel straw from 2,800 kg to 4,200 kg, preferably 3,498 kg core (sugar plus starch) of an appropriate size. Moisten with the 10% Povidone (PVP K30) solution (preferably 1,000 kg) obtained in 1.6) using a compressed air gun, and as it moistens, add the mixture obtained in 1.5) whose weight is preferably 0.751 kg, and which contain the Tromethamine Ketorolac analgesic agent. 1.8) Then add another 50% by weight (preferably 0.251 kg) of the yellow talc obtained in 1.4), previously sieved in a 0.600 mm mesh in order to eliminate the grains.

1-9) Choose the microgranules obtained in 1.8) by having them sifted to eliminate any grain that may have formed. Considering the elimination of grains, the weight of the final product will be from 3,680 kg to 5,520 kg, preferably 4,600 kg.

1.10) Dry the microgranules obtained in 1.9) by means of a greenhouse heat supply at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours.

Step 2): Manufacture of the antiospasmodic release granules of the antiospasmodic Hioscin or Pargeverine comprising the following substeps:

2.1) Dissolve in a suitable shaking vessel of 1,000 gal, 525 g, preferably 1.271 g tartrazine yellow dye, 0.990 g to 1.490 g, preferably 1.241 g bright blue dye, and from 0.018 kg to 0.031 kg, preferably 0.025 kg of purified water.

2.2) Add after dissolution of the dyes under stirring from 0.009 Kg to 0.015 Kg, preferably 0.012 Kg of isopropyl alcohol.

2.3) Place in a container with a suitable capacity for

0,400 kg to 0,600 kg, preferably 0,500 kg of talc and add the dyes obtained in 2.2), stirring until the mixture is homogenized. The resulting talcum will be green.

Dry the mixture obtained in 2.3) at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours. 0 weight of this mixture of talc and colorants will be of 0,402 kg to 0,602 kg, preferably 0.502 kg. Mix 0.400 kg to 0.600 kg, preferably 0, 500 kg of Hyoscine or Pargeverina 50% by weight (preferably 0.251 kg) of ^"talc green obtained in 2.4), previously sieved in a mesh of 0.600 mm in order to eliminate the grains.

Prepare in a suitable container 10% Povidone (PVP K30) solution by dissolving with stirring to a clear solution of 0.080 Kg to 0.120 Kg, preferably 0.100 Kg of Povidone (PVP K30) with 0.700 Kg to 1200 Kg, preferably 0.900 kg of isopropyl alcohol, obtaining from 0.780 kg to 1.320 kg, preferably 1.000 kg of 10% Povidone solution (PVP K30).

Place in a suitable capacity stainless steel straw of 2,800 kg to 4,200 kg, preferably 3,498 kg of core (sugar plus starch) of an appropriate size. Moisten with the 10% Povidone (PVP K30) solution (preferably 1 000 Kg) obtained in 2.6) with the use of a compressed air gun, and as it moistens, add the mixture obtained in 2.5) which weight is preferably 0.751 Kg, and which contains the antiospasmodic agent Hioscin or Pargeverine.

2.8) Then add the other 50% by weight

(preferably 0.251 kg) of the green talc obtained in 2.4), previously sieved in a 0.600 mm mesh in order to eliminate the grains.

2.9) Choose the microgranules obtained in 2.8) by having them sieved to eliminate any grain that may have formed. Considering the elimination of grains, the weight of the final product will be

3,680 kg to 5,520 kg, preferably 4,600 kg.

2.10) Dry the microgranules obtained in 2.9) by means of a greenhouse heat supply at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours.

The formula or composition for a batch of 46,000 doses each containing microgranules of the Tromethamine Ketorolac analgesic is as follows:

Tromethamine Ketorolac: from 0.300 kg to 0.700 kg, preferably 0.500 kg

Povidone (PVP K30): from 0.080 Kg to 0.120 Kg, preferably 0.100 Kg

Talc: from 0.400 Kg to 0.600 Kg, preferably 0.500 Kg Tartrazine Yellow Dye: from 2.130 g to 2.890 g, preferably 2.512 g

Core (sugar and starch): from 2,800 kg to 4,200 kg, preferably 3,498 kg

Purified Water and Alcohol Isopropyl compounds are not present because they are volatile components.

The formula or composition for a batch of 46,000 doses each containing microgranules of the antiospasmodic Hioscin or Pargeverine is as follows:

Hyoscine or Pargeverine: from 0.400 kg to 0.600 kg, preferably 0.500 kg;

Povidone (PVP K30): from 0.080 Kg to 0.120 Kg, preferably 0.100 Kg;

Talc: from 0.400 kg to 0.600 kg, preferably 0.500 kg; Tartrazine Yellow Dye: from 1,000 g to 1,525g, preferably 1,271g;

Bright Blue Dye: 0.990. g to 1.490 g, preferably 1.241g;

Core (sugar and starch): from 2,800 kg to 4,200 kg, preferably 3,498 kg;

Purified water and isopropyl alcohol are not present as they are volatile components.

Example of capsule composition with both active agents

Composition of the contents of each capsule with immediate-release microgranules of the Tromethamine Ketorolac analgesic and programmed-release microgranules of the antiospasmodic Hioscin or Pargeverine:

Tromethamine Ketorolac: 2.5% to 15% by weight;

Hyoscine or Pargeverine: 2 _: 5% to 15% by weight;

Povidone (PVP. K30): 1% to 5% by weight; White talc: 5% to 30% by weight;

Dyes (Yellow + Green): 0.03% to 0.06% by weight;

Core (sugar and starch): 87.97% to 29.94% by weight;

Coating Polymers: 1% to 5% by weight;

The sum of the weight percentages of each component should be 100%.

Undoubtedly, as soon as the present patent application is put into practice, embodiments of the above illustrated example may be introduced without departing from the fundamental principles clearly set forth in the following claim clauses.

Claims

1. "PHARMACEUTICAL COMBINATION MANUFACTURING PROCEDURE CONTAINING ANALGESIC AGENT AND ANTIESPASMODIC AGENT", comprising the following steps for the manufacture of a batch of 46,000 doses of each active agent: Step 1): Manufacture of immediate release microgranules of Cetorolaco analgesic of Tromethamine comprising the following substeps: 1.1) Dissolve in a suitable vessel under strong stirring 2.130 g to 2.890 g, preferably 2.512 g of tartrazine yellow dye and from 0.020 Kg to 0.030 Kg, preferably 0.025 Kg of purified water; 1.2) Add after dissolution of the dye under stirring from 0.009 kg to 0.015 kg, preferably 0.012 kg isopropyl alcohol; 1.3) Place in a container with a suitable capacity of 0,400 kg to 0,600 kg, preferably 0,500 kg of talc and add the dye obtained in 1.2) while stirring until the mixture is homogenized; 1.4) Drying the heat obtained from a greenhouse the mixture obtained in 1.3) at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours, resulting in the weight of this talc and dye mixture of 0.400. Kg to 0.600 kg, preferably 0.502 kg; 1.5) Mix from 0, 300 Kg to 0.700 Kg, preferably 0.500 Kg of 50% by weight Tromethamine Ketorolac, preferably 0.251 Kg of the yellow talc obtained in 1.4) previously sieved in a 0.600 mm mesh in order to eliminate the grains; 1.6) Prepare in a suitable container a solution of Povidone (PVP K3C) to 10% by dissolving under stirring to a clear solution of 0.080 Kg at 0.120 Kg, preferably 0.100 Kg of Povidone (PVP K30) with 0.700 Kg to 1,200 Kg, preferably 0.900 Kg of isopropyl alcohol resulting in 0.780 Kg a 1,320 kg, preferably 1,000 kg of 10% Povidone solution (PVP-K30); 1.7) Place in a stainless steel straw of a suitable capacity of 2,800 kg to 4,200 kg, preferably 3,498 kg core (sugar plus starch) of an appropriate size, and moisten with 10% Povidone solution (PVP K30), preferably 1,000 Kg obtained in 1.6) with the use of a pistol; of compressed air and as it is moistened to add the mixture obtained in 1.5) whose weight is preferably 0.751 kg and which contains the Ketorolac Tromethamine analgesic agent; 1.8) Then add the remaining 50% by weight, preferably 0.251 kg of the yellow talc obtained in 1.4) previously sieved in a mesh of 600 mm in order to eliminate the grains; 1.9) Select the microgranules obtained in 1.8) so that they are sieved to eliminate any grains that eventually formed resulting in the elimination of grains a weight of the Tromethamine Ketorolac microgranules from 3,680 Kg to 5,520 Kg, preferably 4,600 Kg; 1.10) Dry the microgranules obtained in 1.9) by means of a greenhouse heat supply at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours; Step 2): Manufacture of the antiospasmodic Hioscin scheduled release microgranules comprising the following substeps: 2.1) Dissolve in a container suitable under strong agitation of 1,000 g to 1,525 g, preferably 1,271 g of tartrazine yellow dye, of 0,990 g to 1,490 g, preferably 1.241 g of bright blue dye and from 0.018 kg to 0.031 kg, preferably 0.025 kg of purified water; 2.2) Add after dissolution of the dyes under stirring from 0.009 kg to 0.015 kg, preferably 0.012 kg isopropyl alcohol; 2.3) Place in a container with a suitable capacity of 0.400 kg to 0.600 kg, preferably 0.500 kg of talc and add the dyes obtained in 2.2) while stirring until the mixture is homogenized resulting in a green colored talc; 2.4) Drying the heat obtained from a greenhouse the mixture obtained in 2.3) at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours, resulting in the weight of this mixture of talc and dyes of 0, 402 kg to 0.602 kg, preferably 0.502 kg; 2.5) Mix from 0,400 kg to 0,600 kg, preferably 0,500 kg of 50% by weight hyoscine, preferably 0,251 kg of green talc obtained in 2.4) previously sieved in a 0,600 mm mesh to eliminate the grain. ; 2.6) Prepare a 10% solution of Povidone (PVP K30) in a suitable container by dissolving with stirring to a clear solution of 0.080 Kg to 0.120 Kg, preferably 0.100 Kg of Povidone (PVP K30) with 700 Kg. at 1,200 kg, preferably 0.900 kg of isopropyl alcohol resulting from 0.780 kg to 1.320 kg, preferably 1,000 kg of 10% Povidone (PVP K30) solution; 2.7) Place in a stainless steel straw of a suitable capacity of 2,800 kg to 4,200 Kg, preferably 3,498 Kg of core (sugar plus starch) of appropriate size and moisten with 10% Povidone (PVP K30) solution, preferably 1,000 Kg obtained in 2.6) using a compressed air gun and as it is moistened to add to the mixture obtained in 2.5) whose weight is preferably 0.751 kg and which contains the antiospasmodic agent hyoscine; 2.8) Then add the other 50% by weight, preferably 0.251 kg of green talc obtained in 2.4) previously sieved in a mesh of 0.600 mm in order to eliminate the grains; 2.9) Choose the microgranules obtained in 2.8), so that they are sieved to eliminate any grains that may have formed, resulting in the elimination of grains a weight of Hyoscine microgranules from 3,680 kg to 5,520 kg, preferably 4,600 kg; 2.10) Dry the microgranules obtained in 2.9) by furnishing heat from a greenhouse at a temperature of 45 ± 5 ° C for 8 to 16 hours, preferably 12 hours:

2. "PHARMACEUTICAL COMBINATION MANUFACTURING PROCEDURE CONTAINING ANALGESIC AGENT AND

ANTIESPASMODIC AGENT "according to claim 1, characterized in that the programmed release microgranules manufactured in step 2) are of the Pargeverine antispasmodic.

"PHARMACEUTICAL COMBINATION" according to claim 1, characterized in that it contains microgranules of the immediate release Tromethamine Ketorolac analgesic and microgranules of the programmed release antiospasmodic hyoscine; considering for a lot of 46,000 doses each containing microgranules of the Tromethamine Ketorolac analgesic the following composition: 0.300 Kg to 0.700 Kg, preferably 0.500 Kg of Tromethamine Ketorolac, 0.080 Kg to 0.120 Kg, preferably 0.100 Kg ^' of Povidone (PVP K30), from 0.400 Kg to 0.600 Kg, preferably 0.500 Kg of Talc, from 2,130 g to 2.890 g, preferably 2.512 g of Tartrazine Yellow Dye and from 2,800 Kg to 4,200 Kg, preferably 3.498 Kg Core (sugar and starch); considering for a batch of 46,000 doses each containing micrograms of the scheduled release antiospasmodic Hioscin the following composition: from 0.400 Kg to 0.600 Kg, preferably 0.500 Kg of Hioscin, from 0.080 Kg to 0.120 Kg, preferably 0.100 Kg Povidone (PVP K30) from 0.400 Kg to 0.600 Kg, preferably 0.500 Kg of Talc, 1.000 g to 1.525 g, preferably 1.271 g of Yellow Dye Tartrazine, 0.990 g to 1.490 g, preferably 1.241 g of Blue Dye Brilliant and from 2,800 kg to 4,200 kg, preferably 3,498 kg Core (sugar and starch).

4. "PHARMACEUTICAL COMBINATION" according to claim 3, characterized in that the contents of each capsule with immediate release microgranules of the Tromethamine Ketorolac analgesic and antiospasmodic programmed release microgranules have the following composition: 2.5% at 15 ° C Tromethamine Ketorolac, 2.5 wt.% to 15 wt.% Hyoscine, 1 to 5 wt.% Povidone (PVP K30), 5 to 30 wt.% White Talc, 0.03 wt.% Q, 06% by weight of dyes (yellow + green), 87.97% to 29.94% by weight of core (sugar and starch) and 1% to 5% by weight of coating polymers.

"ICA PHARMACEUTICAL COMBINATION" according to claim 4, characterized in that the programmed release microgranule content of each capsule is of the antispasmodic Pargeverine.