MXPA98007097A - Production of pharmaceutical formulations for the treatment of edema and veno disorders - Google Patents

Abstract

The present invention relates to a medicine that contains a standardized dry extract of seeds of horse chestnut, which is active against various types of edema and diseases of the venous circulatory system and to a process for the manufacture of this medicine. The dried seed extract is processed into the form of pellets which can be coated to obtain sustained release of the agent. In this way, satisfactory therapeutic blood levels of the triterpene glycosides are achieved as the agent. The finished medicament according to the invention can be better provided as a hard gelatin capsule or a matrix tablet containing the pellets of the extrac

Description

PRODUCTION OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT OF EDEMA AND VENOUS DISORDERS BACKGROUND OF THE INVENTION Medicines containing horse chestnut extract (HCE) are usually derived from the seeds of the horse chestnut, for example seeds of Aesculus hippocastanus. Such medicines have been described in the pharmaceutical literature, for example in the reference of the German doctors "Rote Liste", (1967), page 1333. Pharmaceutical products containing horse chestnut extract (HCE) have been manufactured in the form of soft gelatine capsules, ointments, liquid formulations, ampoules or vials for injection, dragees or suppositories. Many scientific investigations have been carried out in order to establish the active ingredient in the extract of horse chestnut (HCE), that is, the agent responsible for the biological effect on the venous system. These investigations have revealed that escin, a specific triterpene glucoside, is the essential agent of pharmacological action. In the model REF. 28201 animal and human pharmacological has been shown that, after administration of horse chestnut extract (HCE), the permeability of capillary vessels involved in venous and edemic disorders, is decreased by 22% compared to the control not treated or treated with placebo, see Pashinger, E. Witz and E. Zwerger, Med. Welt, 32, (1981), pgs. 1954 and subsequent. Studies carried out on the administration of horse chestnut to treat post-traumatic edema such as edema after wounds, cerebral edema, thrombophlebitis and other disorders of the circulatory system (for example venous insufficiency) revealed that the quality and action of those conventional simple compositions, were not satisfactory. It was recognized that the release rate of the active ingredient needed improvement due to its irregular and unreliable behavior in the bloodstream and its short duration action. Prolonged action and regular therapeutic levels in the bloodstream (when the drug is administered in the solid form) can be achieved in a number of different ways. For example, multilayer tablets, in the embedded or matrix forms, molded tablets, "extrusion coated" tablets, or so-called pellet preparations, all of which after administration show more or less sustained release of the agent, in different sections of the gastrointestinal tract according to drug designs specific to the characteristics of the agent and to the ingredients, as well as the particular preparation technique. Since the early 1950s attempts have been made to develop the extended-release products. Since then, the manufacture of pellets has been the subject of intense research, in particular with the development of innovative formulations. Conventionally, the word "pellet" has been used to describe a variety of geometrically defined agglomerates, systematically produced, comprising the drug and different ingredients such as binding agents, carriers, and if necessary, specific coatings. The formation of pellets or granulation among other things is a process of agglomeration that converts fine powders or granules of bulk drugs and excipients, into small free-flowing, spherical or semi-ferric units which are referred to as pellets. These are in the size range, typically, between 500 and 1500 μm, but diameters of less than 500 μm can also be used. Some of the processes of forming pellets widely used in the art are extrusion methods or feronization. In addition, from this process, the formation in layers by solution / suspension or the formation in layers by dust is also used. Pellets are very important in the pharmaceutical industry for various reasons. Products formed into pellets do not only show flexibility in the dosage form, in design and development, but are also used to improve the safety and potential of an almost ideal bioavailability of drugs. When the pellets containing the active ingredient are administered in vivo in the suspension form, capsules or disintegration tablets, these have significant therapeutic advantages over the single unit dose forms. Because the pellets are freely dispersed in the gastrointestinal tract, they maximize drug absorption, reduce peak plasma fluctuations and minimize potential side effects without significantly reducing the bioavailability of the drug. This type of unit dose form also reduces variations in gastric emptying rates or rates and in full transit times. In this way the undesirable variability of plasma profiles is minimized, which is common with other conventional dosage forms such as single dose drugs in the form of simply compacted tablets or dragee cores. An additional advantage of pellets over conventional single unit dose forms, as indicated above, is that high local concentrations of the drugs, which may be inherently irritant or anesthetic with conventional sustained release medicaments, can be avoided. The controlled release pellets are prepared either to distribute the drug at a specific site within the gastrointestinal tract, or to sustain the action of the drugs over a prolonged period of time. Yet another advantage of the manufacture of pellets is an enormous flexibility during the development of oral dosage forms for example, pellets composed of different pharmacological entities can be mixed and formulated in a simple dosage form. This procedure allows the combined distribution of two or more drugs that may or may not be chemically compatible, at the same or different sites within the gastrointestinal tract. A combination of pellets of different drugs, which optionally have different release rates, administered as a single dose, can be distributed to the same area or optionally in different sections of the gastrointestinal tract. In addition, the pellets have a low ratio of surface area to volume, and provide an ideal form for the application of film coatings. It is important that pellets of reproducible weights can be achieved to load the capsules, in order to conform to the regulations of the Good Manufacturing Practices (GMP) of the FDA. As alternatives to the above pellet forming processes are other conventional methods that include conventional methods such as globulation, balling or compression. As a first step of pellet formation, a conventional granulation process is followed «W? ~~ t * 3 > gje < ? * -gyr, ^ »-« - w > * "~ t &! ' g $ gjt I &!?.. SBÍK * lg F 'by blebbing or Feroni tion arise, however, various problems depending on the specific drugs that will be formed into pellets In particular plant extracts tend to agglomerate before processing , usually because of their hygroscopicity. additional problems may arise in coating the pellets to achieve sustained release for speeds reproducible release. can be used pellets matrix instead of the pellets covered. the pellets in matrix have the drug embedded in a matrix of lipid substance or polymers where one or more bioactive agents are released into the gastrointestinal tract by erosion. in contrast to this erosion form, the active ingredient is released through the membrane permeable coating, water insoluble , porous, fine, of the coated pellet mentioned above, the coating consisting, for example or, of polymers constituted by monomeric units of unsaturated organic acids. This form shows a mechanism that is substantially unaffected by pH, by the concentration of ions or by the enzymatic activity in the gastrointestinal tract. Coated pellets that have this mechanism of release independent of pH, are called diffusion pellets which after their uptake are distributed within the gastrointestinal tract and gradually release the respective agent through the micropores of a suitable polymeric coating. Among the previous pharmaceutical compositions containing the horse chestnut extract (HCE), the pellet form was chosen to study its applicability for the development of a drug, based on that vegetable extract having an improved quality, in particular superior safety pharmacological and bioavailability. It has been shown that the choice for an agent release system, independent of pH, which is a coated pellet form, causes a number of additional problems and drawbacks. The investigations carried out have shown that the type and composition of the horse chestnut extract (HCE) and the additives used to form and spheronize the pellets, presents problems for the consistency of the surface of the pellet, that is to say for its uniformity, for example regarding its ideal ball or globule shape.

Pellet processing usually leads to uneven, rough and uneven surfaces and a wide average grain size distribution of the pellets to be manufactured. This also leads to mechanical problems such as blockage of the parts of the machine or undesired agglomerations during the formation of the pellets. Conventional extracts of chestnut (HCE) obtained by drying the extracted seed material over heated drums or under reduced hotbox pressure are especially prone to cause considerable mechanical problems pelletization, which can give as result blocked devices. This results in lost lots and non-productive work hours. It has been found that the processes of conventional pellet formation using common extract materials are very expensive and not economic. In addition, the safety of the drug was not found to be satisfactory and no desired release rates were obtained. Studies have revealed that there are many problems associated with the irregular shape and surface of the pellet, which leads to unforeseen disadvantageous properties of the finished pellets. Problems have been found to influence release rates, so that a substantial amount of the material successfully processed into pellets, made from the extract of conventionally dried seeds, is rejected because the batches do not conform to pharmacological quality standards. necessary. This is the case for Coated sustained release pellets, made from conventionally prepared seed extract, which have an irregular shape. These drawbacks lead, among other things, to problems in the encapsulation of the pellets containing the active ingredient or the active principle, by causing undesirable deviations in the dosage. In addition, it has been recognized that these problems deteriorate the quality of the drug and its safety, as well as economic losses, undue energy consumption, lost machine time (in which the machines are out of action for prolonged periods after blockage). and during cleaning) and additional transportation costs, etc.

OBJECTIVES OF THE INVENTION Therefore, a first objective of the present invention is to provide a method that allows the standardization of the horse chestnut extract (HCE) pellets. A further objective of the present invention is to provide a method for producing high quality pellets containing escin as an active ingredient, which pellets have improved safety and optimized bioavailability (allowing the provision of continuous therapeutic blood levels in a reproducible manner). Yet another objective of the present invention is to provide a pharmaceutical formulation containing horse chestnut extract (HCE) which has improved quality, consistency and surface properties. Yet another objective of the present invention is to allow the manufacture of a pharmaceutical composition containing escin, in an economical manner, in a form such that the formulation can approach the ideal effect desired in the therapeutic treatment of post-traumatic edema and disorders of the venous circulatory system.

A further objective of the invention is to provide an extract formulation of horse chestnut (HCE) whose active unit doses can have minimum weight and dimensions, so that the compliance of the patient is not impaired by large tablets or capsules difficult to ingest. On the other hand, the weight and minimum dimensions of pharmaceutical containers would save weight to be transported and stored, so that energy consumption could be reduced for ecological and economic reasons. In this context, the ecological objective is to reduce the total amount of waste or waste, which is an increasingly serious problem worldwide.

BRIEF DESCRIPTION OF THE INVENTION The objects of the invention can be achieved according to the invention by the method of producing a pharmaceutical formulation (suitable for administration, inter alia, in capsule form), containing the escin formulation as the pharmaceutically active ingredient, for the treatment or prophylaxis of venous circulatory disorders, various types of edema, or inflammation. The formulation is prepared by a process comprising the following steps: (a) extraction with solvent of the seeds of horse chestnut; (b) mixing the resulting solvent extract, with dextrin; (c) drying the resulting mixture to form particles; (d) mixing the particulate mixture with additional dextrin, a pharmaceutically acceptable binder and a pharmaceutically acceptable filler; (e) the formation of pellets of the resulting mixture, such as pellets having a particle size in the range of 500 to 1700 microns; and (f) coating the resulting pellets, in substantially dry form, with a pharmaceutically acceptable acrylate polymer.

The above method provides pellets with sustained release of the active ingredient in the bloodstream, by providing coated pellets. These are suitable for the production of formulations for therapeutic administration and »R» * ^ * ^ rf * 't' «aa-gW ^ qB ^ fl ^ JS-6 ^^ t? > r * rwf? rfiR "* '&prophylactic in case of the above medical indications, in particular also for patients suffering from cerebral edema or swelling of different genesis.

DESCRIPTION OF THE PREFERRED MODALITIES 1) Preparation of dried horse chestnut extract (HCE) by means of steps (a) to (c): milling of the seeds of horse chestnut to a maximum particle size of 6 mm and a minimum particle size of 0.3 mm, macerating and percolating then the ground seeds with a mixture of alcohol and water as solvent, the alcohol content of 35 to 65% v / v for 1 to 2 days, the temperature being 30 to 40 ° C (86 to 104 ° F), to obtain a tincture of horse chestnut extract (HCE), with which 1500 kg a 2000 kg of seed material are extracted with 4000 to 5000 liters of total solvent;(ii) the concentration of the liquid tincture of horse-chestnut obtained in this way, under reduced atmospheric pressure, by evaporation at a temperature of 45 to 60 ° C (113 to 140 ° F) up to a total dry residue content of 50 % to 63% weight / weight in the liquid extract obtained; iii) the addition of dextrin in a proportion of 1 to 20 kg per 100 kg total dry substance calculated based on the liquid extract obtained according to step ii) above; optionally together with demineralized water in an amount such as to adjust the spray-drying solution to a total dry substance content of 38 to 49% w / w, and a triterpene glucoside content of 15 to 20% w / w in the dry extract, calculated on the basis of the typical pharmaceutically active agent, escin, to prepare the liquid extract for spray drying. iv) the spray drying of the preceding liquid mixture at a temperature of 40 to 60 ° C (104 to 140 ° F), the air inlet having a content of 02 less than 10% and a temperature of 180 to 210 ° C (365 to 410 ° F), the outlet air having a temperature of 75 to 95 ° C (167 to 203 ° F); 2) the preparation of the pellets via steps (d) and (e): v) addition a) from 10 to 30 parts by weight of dextrin a b) the free-flowing, spray-dried extract obtained through step iv) above, to an amount of 90 to 7 O * parts by weight of total dry substance, so that the complete mixture to be formed in pellets have a standardized total content of 15 to 19% w / w of triterpene glycosides, calculated again based on the typical escin agent; ___ vi) mixing the above standardized mixture of a) dextrin and b) the spray dried extract together with c) polyvinylpyrrolidone, for example povidone or a vinylpyrrolidone and vinyl acetate copolymer having an average molecular weight of 40,000 to 80,000 (calculated by the light scattering method) and d) talc, so that the proportion by weight is in w / w 0.5-10 parts of a): 50-150 parts of b): l-15 parts of c): 0.5-10 parts of d); vii) the granulation / pelletization of the mixture of a): b): c): d) by the addition of an alcohol to wet the mixture in a mixing / granulating apparatus or a feronizer or other commercial forming machine pellets; viii) drying the wet material, formed in pellets, in a dryer using a split recirculation air stream, coming from the dryer where the inlet temperature should not exceed 70 ° C (158 ° F) being the temperature of the extreme point Output of at least 45 ° C (113 ° F): ix) sieving the dry material in the form of a pellet, to obtain a size in the specification range of 500 to 1700 μm; the coating of the pellets via step (f) to obtain its prolonged action: x) coating the strands screened by the spray technique, by means of an acrylate mixture, for example poly (ethylacrylate, trimethylammoniumethylmethacrylate methacrylate) chloride having an average molecular weight within the range of 120,000 to 180,000 dissolved in a mixture of organic solvents together with small amounts of a plasticizer such as triacetin, triethyl citrate or dibutyl phthalate, so that the portion of the coating calculated on the basis of the total weight of the pellet is within the range of 2.5. at 5.0% p / p and finally) the preparation of the final medication xi) filling the pellets covered in lower parts of hard gelatin capsules, closing the capsules by means of the gelatin top parts, and then sealing the blister package or alternatively producing a sustained release matrix tablet by compacting the coated pellets together with the usual pharmaceutically acceptable ingredients, such as a disintegration matrix carrier. These formulations may optionally contain additional agents in pellet form or processed in their respective powder form.

The quantity of pellets that are to be encapsulated or compacted to tablets is calculated in such a way that each capsule contains 20, 25, 30, 50, 75, 100 or 150 mg of triterpene glucoside as agent, which is calculated as escina , for example 200 mg of pellet material can be filled into relatively small capsules if the triterpene glucoside content is only 15%, see step v) -b), to achieve a dose amount of 30 mg agent, for example, coated pellets of approximately 278 mg, for encapsulation, which are sufficient to give a unit dose of sustained release of 50 mg of triterpene glucoside calculated as escin if the triterpene content of the coated pellet is at the upper limit of 18%. The combination of the steps and materials used to produce the pellets, together with the specific formula for the calculation of the amount of material needed in the various stages, all help the production of pellets with improved release rates, better surface properties, high performance and a better quality of the operation of the drug. The standardization of the triterpene glycosides contained within the extract helps to produce the consistency from batch to batch, which is a guarantee of the uniformity of the doses. It is specifically the addition of the dextrin at least in one step, preferably in proportions and defined and calculated amounts, which improves the safety of the drug and improves the properties of the pellets. According to the invention, dextrin is used to prepare the dried extract from horse-chestnut seeds, to obtain a free-flowing material which is standardized in terms of the active ingredient escin (which is used as a substance of the invention). reference). Dextrin also makes the mixture of dry extract suitable for the subsequent step of pellet formation. Dextrin can be used for a two-step standardization based on escin. Optionally, the main amount of dextrin, which is used as the amount of standardization and additive in both steps, can be added to the mixture for the formation of pellets. The particular steps, the proportion and the amounts of dextrin as processed according to the invention, also considerably improve the flow and pelletizing properties of the horse chestnut extract (HCE). Despite the improved properties, no problems of de-mixing of the pellets have been found. Surprisingly, dextrin has a positive impact at high densities and in the compaction of the extract, so that globulization is significantly improved to form pellets with a high density, with improved resistance to abrasion or crushing. By the method according to the invention an ideal pharmaceutical composition is provided, for the treatment of various forms of edema, disorders and diseases of the circulatory and venous system, swelling or swelling, inflammation or for the improvement of the anticoagulant action.

DESCRIPTION OF THE DRAWINGS Figure 1 shows a flow diagram representing the preparation of the liquid extract of seeds of the horse chestnut by means of a mixture of aqueous solvent and the evaporation of the tincture obtainable by maceration and percolation of ground seeds of horse-chestnut, according to the invention, as reflected in the steps described above i) to ii); Figure 2 shows, according to the invention, the preparation of the dried extract by free flow spray of seeds of horse chestnut, including the alternative features of the addition of greater or lesser amounts of dextrin, the latter optionally being an additive * mr s 9ß M & amp; ^ '* met3 > i3! ff * tt < z! p? 7 - ^ of standardization, as reflected by the previous steps ii) to iv); Figure 3 shows the preparation of the uncoated pellets, for example without lacquer from the extract of horse-chestnut seeds, which contain triterpene glucosides as agent, the standardization of which is based on the alternative routes according to the steps v ) to ix) according to the invention.

Figure 4 shows the coating, for example, lacquering of the pellets of the horse chestnut seed extract, to give the sustained release form that can be used for the manufacture of drug ready for administration.

More specifically, the method according to the invention consists of the following manufacturing steps, which are illustrated in more detail below: DETAILED DESCRIPTION OF THE INVENTION 1) Preparation of the dry extract of horse chestnut seeds (HCE): i) the seeds of horse chestnut are ground to give between 6 mm and a minimum particle size of 0.3 mm, but preferably at a range of 5.0 to 1.0 m . This is carried out in a conventional plant-cutting mill for plant drugs. The ground seeds of horse chestnut are then, in a period of 1 to 3 days, preferably 2 days, macerated and percolated using a mixture of alcohol and demineralized water as the solvent, with the alcohol content being 35 to 65% v / v, but preferably 40 to 45% v / v isopropanol, ethanol or methanol and the temperature which is 30 to 40 ° C (86 to 104 ° F). The result is a tincture of horse chestnut extract (HCE), whereby 1500 to 2000 parts by weight, for example 75 to 100 kg of seed material, preferably 1750 parts by weight of seeds are extracted with 4000 to 5000 parts by volume, for example 200 to 250 liters, preferably 4500 parts by volume of total solvent (by which can also be understood, based on the system cgs instead of kilograms and liters, also for example grams and mi 1 illitros) . The final dyeing is allowed to stand overnight, so that the insoluble particles can be decanted and the resulting clarified dye is filtered using a conventional chamber press. ii) The obtained liquid tincture of horse-chestnut is concentrated under reduced atmospheric pressure, by evaporation in a conventional film evaporator at a temperature of 45 to 60 ° C (113 to 140 ° F), preferably 55 ° C (131 ° F) ), until a total residue content of 50% is obtained at 63% w / w, for example 57% w / w in the liquid. iii) The dextrin is then added to the liquid extract which is concentrated in a proportion of 2 to 25 parts by weight, preferably 4 to 12 parts by weight per 100 parts by weight of total dry substance, calculated on the basis of the preceding liquid extract, optionally - depending on a high percentage of dry substance in the above liquid concentrated extract - demineralized water is added to the mixture of the liquid extract plus the dextrin, in an amount such as to adjust the spray-drying solution to a total dry substance content of 38 to 48% w / w, preferably 42 to 46% w / w and a triterpene glucoside content of 15 to 20% w / w, preferably 17 to 19a% w / w in the dry extract comprising the total dry substance to be prepared, calculated on the basis of the typical pharmacologically active agent, escin, to prepare the liquid extract for spray drying; whereby a greater amount of dextrin, for example 25 parts by weight, is used if the triterpene glucoside content is standardized before spray drying and vice versa, a smaller amount of dextrin is incorporated in the spray solution without standardization of the triterpene glycosides, calculated as escin is carried out in the next step 2), to manufacture the extract pellets; iv) The above liquid mixture is spray dried at a solution temperature of 40 to 60 ° C (104 to 140 ° F), preferably 45 to 55 ° C (113 to 131 ° F), the air inlet having a 02 content < 10% and a temperature of 180 to 210 ° C (356 to 410 ° F), preferably 190 to 205 ° C (374 to 401 ° F), the air outlet having a temperature of 75 to 95 ° C (167 to 203) ° F), preferably 80 to 92 ° C (176 to 198 ° F); preparation of the horse chestnut pellets: v) the material that is going to be formed into pellets is mixed as follows: a) 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight of dextrin together with b) the free-flowing spray dried extract, obtained through the preceding step iv), up to an amount of 90 to 70 parts by weight of total dry substance, so that the complete mixture to be pelletized has a total standardized content of 15 to 19% w / w, preferably 16 to 18% w / w triterpene glucosides, calculated again based on the typical active ingredient escin; the above standardized mixture of a) dextrin and b) spray dried extract, is further mixed perfectly together with c) polyvinylpyrrolidone, for example, povidone or preferably a copolymerized vinylpyrrolidone and vinyl acetate, for example polyvidone acetate or co-povidone, having an average molecular weight of 40,000 to 80,000, preferably 45,000 to 75,000 VP / VA copolymerized 60/40 (calculated by the light scattering method) and d) talc, so that the weight ratio is w / w preferably 1-6 parts of dextrin a): 60-100 parts of free-flowing spray-dried extract b): 2-10 parts PVP or copolymerized c): 1-5 parts of talc d); vii) subsequently the mixture in the form of powder a): b): c): d) as it is manufactured according to preceding step vi), is moistened with e) alcohol, preferably isopropanol in a mixer / granulator or macerator apparatus, is feronizer or other conventional pelletizing machine, preferably a high shear mixer, up to an amount of about 15 to 30 parts of d) w / w as alcohol whose step involves spraying alcohol onto the material to begin the granulation and adjust the speed of the mixer and the speed of the shredder in a manner such as to promote the granulation on the one hand, and to inhibit the blocking of the apparatus tools on the other hand. When the formation of the pellets appears slow, additional isopropanol can be applied within the above-mentioned amount range in interspersed portions with the mixing periods, until the desired pellet size distribution is achieved. vii) material in the form of a still wet pellet is dried in a dryer with an air current ssss of split recirculation, with the inlet temperature not exceeding 70 ° C (158 ° F), the temperature of the outlet end point being at least 45 ° C (113 ° F). ? Finally, the dry pellet material is screened to obtain a specification in the range of 500 to 1700 μm, preferably 600 to 1500 μm; 3) coating of the dried and sieved pellets to achieve their prolonged action: x) the dry and sieved pellets are coated with a mixture of acrylates using a spray technique. Suitable acrylates include poly (ethacrylate, methylmethacrylate, trimethylammonium chloride, and methylmethacrylate) having an average molecular weight of from 120,000 to 180,000, preferably 145 to 155,000, which is dissolved in a mixture of solvents, preferably solvents. organics such as ethanol, isopropanol and / or acetone together with small amounts of a plasticizer such as triacetin, triethyl citrate or dibutyl phthalate or other substances that are common for these purposes, and talcum such as microtalc, whereby the appropriate amounts of pellets without lacquer: polymers of acrylic acid: emollient: microtalc: solvent is in the w / w 100 parts: 3-4 parts: 0.25-3.5 parts: 2.7- 3.3 parts: 22-28 parts the ratio of solvents isopropanol: acetone it is within the range 1.2-1.7: 0.8-1.2 w / w whose solvent mixture is sprayed onto the stirred pellets (optionally in the fluid bed) in such a way that the portion of the cap a coating calculated on the basis of the total pellet weight is within the range of 2.5 to 5.0% w / w after which, as a final step 4) the preparation of the final medication continues: xi) the coated pellets are loaded into hard gelatin capsules. The lower part of the capsule is filled and subsequently the capsule is closed by means of the upper part of gelatin; Then the capsules are sealed in blister packs. The quantity of pellets to be encapsulated is calculated in such a way that each capsule contains 20, 25, 30, 50, 75, 100 or 150 mg, preferably 50 or 100 mg of triterpene glucosides as agent, which is calculated as an escin, for example, only 200 mg of the pellet material has to be filled into relatively small capsules if the triterpene glucoside content is only 15%, see step v) -b) above. To achieve a dosage amount of 30 mg of agent or, for example, about 417 mg of coated pellets to be encapsulated, they are sufficient to give a sustained release dose unit of 75 mg of triterpene glucoside, which is considerably increased ( calculated based on escin if the triterpene content of the coated pellet is at the upper limit of 18%). The amounts of dextrin standardization can be • varied and incorporated in step iii) and / or step v). Alternatively, the amount of dextrin needed for standardization purposes can be determined and added in step iii) or step v) and it is best to vary only in one of both steps. Better results of the product are obtained if the amount of dextrin is a fixed and predetermined amount in step iii) in the preparation of the spray mixture, whereby at the same time only a predetermined amount of dextrin is added in step v). , calculated for the standardization, before the manufacture of the pellets. The surprising finding is demonstrated in more detail in the following comparative examples. The following example illustrates the best quality to carry out the invention. Modifications of the invention can be made as claimed, within the abilities of the experts, without departing from the spirit of the invention.

EXAMPLE: Preparation of pellets for dissemination of horse chestnut and manufacture of the finished pharmaceutical composition First the extract, for example, the concentrated tincture of Aesculus hippocastanum was prepared according to the preceding description, as described under paragraph 1), i) and ii), in the detailed description of the present invention, using 10 kg of ground seeds of horse chestnut. This material was then macerated and percolated by means of about 40% by volume of methanol or isopropanol in water as a co-solvent, at a temperature of about 33 ° C (91-92 ° F) with the solvent amount being about 200 liters. The processes of maceration and percolation of the seeds were repeatedly continued until the plant material was more or less exhausted. The extracted horse chestnuts were separated from the tincture and unloaded. The tincture obtained was then decanted and filtered. Liquid extract of horse chestnut (HCE) was prepared by evaporating the previous dye under reduced atmospheric pressure, at a protective temperature of about 45 ° C (110-120 ° F) until a total dry matter residue content of about 55% was obtained; For the preparation of the spray drying mixture dextrin was added to the liquid extract of chestnut Indian (HCE) in a fixed amount of 5 or 20 parts by weight per 100 parts by weight of total dry substance, for example as kilograms, more specifically, 2 kg of dextrin per 20 kg of dry substance, for example approximately 36 to 37 liters of liquid extract, in this case together with the demineralized water in an amount such as to adjust the spray-drying solution to a total content of a dry substance of 45% w / w, which in this example was a amount of approximately 8 liters of water to add to the liquid extract , the resulting triterpene glucoside content being 18% w / w (after removal of the solvent) in the dry extract to be made, calculated on the basis of the typical pharmacologically active agent, escin, for prepare the spray drying solution, see step iii) above. The dried extract was prepared by starting with this mixture in solution according to the conditions of the preceding process described under step iv). A free flowing powder was obtained and homogeneous consistency, the triterpene glucoside content was 19.9% w / w. With this dry, free-flowing horse chestnut extract (HCE), pellets were prepared following the characteristics of the process above, described along the lines of steps v) to ix) under paragraph 2): An amount of 9 kg of the spray-dried extract thus obtained was mixed together with an amount of standardization of the dextrin , which in this case it was approximately 180 grams for ^ u?,? ™? OT »?? m?« A? ^ TO «» f¡ «rys ^^.; and * ßa »ße * fm < r * v < * g, "f * iar" T * "" "~ • .- -» »* Wft achieve a final content of triterpene glucoside of 17% w / w in the pellets ready for administration, and the other components such as copovidone or polyvidone acetate in a suitable amount such as about 300 grams, and talc in a suitable amount such as 150 grams. All these components were perfectly mixed together, then an amount of alcohol such as ethanol or isopropanol was sprayed onto this powder mixture. A commercial high-cut mixer was used for the formation of the pellets, and was operated in such a manner as to cause the formation of the desired pellets. The amount of alcohol needed for sufficient moisture levels and effective globuliication was about 2.5 liters in total. The material in the form of a wet pellet was dried, unloaded and sieved to obtain the desired distribution of pellet nuclei. The screened pellets were coated by spraying a suspension of a commercial mixture of poly (ethacrylate, methyl methacrylate, trimethylammonium ethoxy acrylate chloride) having an average molecular weight of about 150,000 dissolved in the alcohol mixture, together with an emollient such as triethyl citrate in amounts - .. «*« & * ... smaller, and microtalc to prevent agglomeration, to obtain a suspension having a total solid substance content of 2 to 4% w / w, based on the cores of pellets without lacquer, for example, 180 -450 grams of solids with relation to the weight of the core of the pellet of approximately 10.5 kg, to achieve a sustained release rate of the 30% coated pellets within the first hour, see description of the previous process, paragraph 3), step x). Alternatively, by varying the amount of the coating substance within the preceding parts in the weight range, which may be outside those limits, if necessary, the sustained release rate may be controlled, for example within the values desired from 25 to 35 or 45% weight / weight within the first hour. Finally, the coated diffusion sustained release pellets were encapsulated as described above under paragraph 4), step xi). In the present example, the triterpene glucoside content was adjusted to 17% w / w, calculated based on the escin reference agent. In order to obtain the required dosage unit of 50 mg of escin as the triterpene glucoside agent, per capsule, the 294 mg coated pellets being within the sieve range of 800 to 1400 μm, which were encapsulated and sealed inside of blister packs (blister). Optionally, the coated diffusion pellets can, in a conventional manner, be compacted to rapidly disintegrate the matrix tablets leaving free the sustained release pellets comprising the escin, in the desired dosage unit such as for example 75 mg each. The pharmaceutical formulations according to the invention may further contain one or more active ingredients that are processed as pellets or contained in the compacted tablet matrix, in combination with pharmaceutically acceptable carriers and other active ingredients. These additional active ingredients may be selected from the group consisting of circulatory drugs, flavonoids, analgesics, diuretics, vitamins and anti-inflammatory agents, in particular these may be selected from the group consisting of triamterene, thiazide, rutozide, esculin, troxerutin, dihydroergotamine. , heptaminol, diclofenac, inositol nicotinate or tocopherol. These combination agents can also be selected from other drugs such as agents that improve blood flow, antiretrovirals, cardiovascular agents, etc.

COMPARATIVE EXAMPLES Five different batches of manufactured pellets were carried out. Lot no. 1 was produced according to the preceding example as diffusion pellets in the following specific process, which characterizes a fixed amount of dextrin which was added as 5 parts • in weight to the spray solution, for example the standardization to a content of 17% of escin was only carried out shortly after in the step to prepare the mixture of pellet formation. Lot no. 2 was repeated with the exception that the characteristic of adding dextrin to the liquid extract was changed. The amount of dextrin was doubled to 10 parts by weight compared to lot no. 1 before spray drying, and reduced by 5 parts by weight in the last preparation step of the pelletizing mixture, for standardization purposes. This means that the standardization of the escin-based agent was carried out partially in step iii) and also partially in step v), to the pelletizing mixture. Also, lot no. 3 was produced in the same manner as lots 1 and 2, with the exception that an even greater amount of dextrin was added to the spray-drying solution, namely 21 parts by weight, while at the same time it was reduced accordingly the amount of dextrin in the preparation of the pelletizing solution. This means that the standardization took place right in step iii) before spray drying. Lot no. 4 was produced according to the preceding lots, however with the exception that the amount of dextrin was drastically increased beyond the sufficient amount as the standardization and powder / pellet additive. This added amount of dextrin in step iii) before spray drying was 30 parts by weight, while the amount of dextrin in step v) was reduced to smaller amounts. Finally, batch 5 was produced according to the above batches, only with the exception that dextrin was not added at all in step iii), but an increased amount of dextrin was used respectively. for the preparation of the pelletizing mixture. The results of these comparative tests are listed in the following table: Run Chart No. Quantity of Release of Quantity of Performance dextrin sperm coating of the pellets added during% not before first time coated spray-dried Lot No. 1 5 parts 31.5 95% 39.4% by weight Lot No. 2 10 parts 35.1 % 85% 41.2% by weight Lot No. 3 21 parts 33, 7% 110% 26.5! by weight Lot No. 4 30 parts 42.4% 120% 26.2 'by weight Lot No. 5 None The surface quality and the consistency of the lot does not. 1 was excellent; the pellets showed a surprisingly round and smooth surface; the surface of the pellets with the batch no. 2 was very round and the surface was still homogeneous; JV5sxjB the pellets of the lot no. 3 showed a surface consistency that was only satisfactory while the surface of the pellet material according to the batch did not. 4 was very poor due to the crude characteristic; the dry extract resulting from column 5, for example lot no. 5, it was so poor that the processing to form pellets could not be performed due to the blockage of the machine; for this reason, data for the pellets was not available from this run. In all lots 1 to 4, the release rates after 1 hour, measured in a commercial tester, were determined. Release rates between 30 and up to 35% are considered acceptable. The comparative percentages of the dry coating substance, also called lacquer, are based on an amount of 100%, which is necessary to obtain a release rate of about 30%. These data show that a fixed amount of 5 parts by weight and also an amount of up to 10 parts by weight of dextrin, added to the spray-drying solution, results in better results. Under these conditions, the standardization of the agent is shifted to step v) to prepare the pelletizing mixture. However, it is noted that an amount of only 5 parts by weight of dextrin to the spray-drying solution leads to an almost ideal coating amount of 100%, precisely of 95%, while the double amount added to the spray solution according to batch 2, reduces the amount of coating needed but leads to , limit to accept the release rate or rate during the first hour. Pellets made according to lot no. 3 show a rate of release that is satisfactory, but their performance even before coating is not acceptable in the sense of economical manufacture. The same holds true with respect to lot no. 4 which produced a deceptive performance, but also an unacceptable rate of release, and in addition too high amounts of expensive coating material.

Additional comparative data: In order to compare the influence of the amount of dextrin added to the spray solution, the bulk density was determined, expressed in grams per milliliter: Addition of dextrin in apparent density in parts by weight grams / milliliter 7 parts by weight 0.48 g / ml 20 parts by weight 0.41 g / ml These comparative data show that against all expectations, bulk density is increased if the amount of dextrin added to the spray drying solution is reduced, and vice versa. The expert could indeed conclude that with respect to the gentle spray dried horse chestnut extract (HCE) the addition of higher amounts of dextrin would increase the density. This result of the process of the invention is completely surprising to the person skilled in the art. It was also completely unexpected that the control and selection of the characteristics of the inventive process could lead to those satisfactory yields in the manufacture of such highly sensitive plant extract, to a safe sustained release product having ideal therapeutic properties, in particular from the fact that the extracts of the seed of a particular Aesculus hippocas tanum are difficult to process. m ?? m? w? wu? rfi ??? JiM m? ^ tm "'i ^^^^, v < ^? vt st st," ww ^ -W »- ^ *» 8 »' - While the invention has been described in relation to the above modalities, it will be understood that further modifications may be made, and it is intended that this application cover any variations, or even adaptations of the inventions, generally following the principles of the invention and including deviations from the present disclosure as they are within the known practice customary in the art, to which the invention pertains, and as it may be applied to the essential features described hereinabove, and as described immediately below in the scope of the invention. - attached reivi ions.

It is noted that in relation to this date, the best method known to the applicant to carry out the invention, is that which is clear from the presertion of the invention.

Having described the invention as above, re eclaims co or propitiates the con - in do in the siquien es:

Claims (18)

REIViNDICACTOND

1. A method for producing a pharmaceutical formulation that ccr. fill escir? as the active pharmaceutical ingredient, for the treatment or prophylaxis of peripheral venous disorders, various types of edema, or inflammation, in which the formulation is stopped by a process, characterized in that it comprises the steps of: Solve the chestnut seed e ndias; (b) mixing the resulting solvent extract with dextrin; < c 'the drying of the r ° z r i a result in a form par :; ulated; 'i' the mixing of particulate inertia with additional dextrin, a pharmaceutically acceptable agglomerate and a pharmaceutically acceptable filler; (e) the formation of pellets of the resulting mixture as pellets having a particle size r the range of 500 to 1 00 micrometers;

The coating of the pellets resuspenses as a pharmaceutically acceptable acrylate polymer. 7. A method according to claim 1, characterized in that the seeds of horse chestnut are ground before extraction with solvent.

3. A method according to claim 2, characterized in sorque the seeds of horse chestnut are mol i d to give a particle size between 6 mm and 0.3 m.

4. A method of conformance with claim 1, characterized because it was extracted with solvent and is carried out using an alcohol.

An example of a problem with reagent 1, characterized in that the solvent ex: concentrated under reduced atmospheric pressure before step (b).

. A method according to claim 1, characterized in that the extract mixture of solvent and dex rin is dried by means of a spray drying technique. '"--ximmmras? Iv ifg ^ -"

7. A method of consistency with claim 1, characterized in that the pharmaceutically acceptable binder comprises polyvinyl rolidone.

A. A method of co-formulating with claim 1, characterized in that the filler is filled with macon ^ • Tente accepts the talc conec.

9. A cc fority method with claim 1, characterized for the fact that the most readily available polymer is selected from the group consisting of polymers of ethyl acrylate, methanolate and ethyl, t " i ltnetacp lato de tr ime 111 arr cr ov de et.lacr.lato ie tr me t ± 1 ammonium,

1. A method in accordance with the reflectance and cac_on 9, ac ac ized due to the acr atrr polymer. acetically acetates or dissolves in a solvent or gnostic fabric with a plastic plast.

11. A method according to claim 10, wherein the plasticizer is selected from the group consisting of triacetin, triethyl acetate and dibutyl phthalate.

12. A method according to claim 1, characterized in that the coated pellets are loaded onto pharmaceutically acceptable capsules.

13. A method for the production of a pharmaceutically acceptable formulation containing escin as a pharmaceutically active ingredient, for the treatment or prophylaxis of venous disorders, venous insufficiency or inflammations, edema including cerebral eaema, or swelling, in the which formulation is prepared by a process characterized in that it comprises the passes: 1) The preparation of the dry extract of Indian ur ur cassava (HCE) by means of pa.c, os (a) to (c). i) milling of the seeds: Indian chestnut with a maximum particle size of 6 mm and a particle size of 0.3 mm, macerating and percolating then the seeds mi '; Going with a mixture of alcohol and water as solvent, the alcohol content being from 35 to 65% v / v for 1 to 2 days, with the temperature being from 30 to 40 ° C (86 to 104 ° F), to obtain a tincture of horse chestnut extract (HCE), whereby 1500 kg to 2000 kg of seed material are extracted with 4000 to 5000 liters of total solvent; i) the concentration of the liquid tincture of horse-chestnut obtained in this way, under reduced atmospheric pressure, by evaporation at a temperature of 45 to 60 ° C (113 to 140 ° F) up to a total dry residue content of 50% to 63% weight / weight in the liquid extract obtained; iii) the addition of dextrin in a proportion of 1 to 20 kg per 100 kg total dry substance calculated based on the liquid extract obtained according to step ii) above; optionally together with demineralised water such amount as to adjust the spray-drying solution to a total dry substance content of 38 to 49% w / w, and a triterpene glucoside content of 15 to 20% w / w and he '•• t *! I & ? & *? &% sr? 1 dry extract, calculated on the basis of the typical pharmaceutically active agent, escin, to prepare the liquid extract for spray drying. iv) spray drying the preceding liquid mixture at a temperature of 40 to 60 ° C (104 to 140 ° F), the air inlet having an O content; less than 10% and a temperature of 180 to 210 ° C (365 to 410 ° F), the outlet air having a temperature of 75 to 95 ° C (167 to 203 ° F); the preparation of the pellets via steps (d) and (e): v) the addition a) from 10 to 30 parts by weight of dextrin ab) the free-flowing, spray-dried extract obtained through step iv) above, to an amount of 90 to 70 parts by weight of total dry substance, so that the entire mixture to be pelletized has a total standardized content of 15 to 19% w / w of tri erpene glycosides, calculated again based on the typical escin agent; i) mixing the above standardized mixture of a) dextrin and b) the spray-dried extract together with c) polyvinylpyrrolidone, for example povidone or an ideal vinyl acetate copolymer and vinyl acetate having an average molecular weight of 40,000 a 80,000 (calculated by the light scattering method) and d) talc, so that the proportion by weight is in p / p 0.5-10 parts of a): 50-150 parts of b): l-15 parts of c) : 0.5-10 parts of d); vil1) granulation / pelletization of the method of a): b): c): d) mean the addition of an alcohol to humidify the mixture in a mechanized or granulator apparatus or a filter or other commercial pellet processing machine; viii) the drying of the wet material, formed in pellets, in a dryer using a split recirculation air stream, coming from the dryer where the inlet temperature should not exceed 70 ° C (158 ° F) being the temperature from the exit end point of at least 45 ° C (113 ° F): ix) sieving the dry material in pellet form, to obtain a size in the specification range of 500 to 1700 μm; the coating of the pellets via step (f) to obtain its prolonged action: x) the coating of the strands screened by means of the spray technique, by means of a mixture of acrylate, for example polychloride (eti lac lato, trimethyl ammonium methacrylate), which has an average molecular weight in the range of 120,000 to 180,000, dissolved in a mixture of organic solvents together with small amounts of a plasticizer such as triacetin, triethyl citrate or dibutyl alato, so that the portion of the coating calculated with er base. the total weight of the pellet is within the range of 2.5 to 5.0% p / p and finally) the production of the final drug xi) the filling of the pellets covered in lower parts of hard gelatin capsules, closing the capsules by e. It was given from the gelatin top parts, and then sealed in blister packs or by compacting the coated pellets together with the pharmaceutically acceptable disinfection matrix components, for sustained release tablets.

14. A method according to claim 13, characterized in that in step iii) the dextrin is added to the spray-drying solution in a fixed amount related to each production batch, while in lp or v) the dextrin is added in amounts such as to give the triterpene glycogen content in the coated diffusion pellets, up to 17%, in step vi) a VP / NA copolymer of 60/40 within the average molecular weight of 45,000 and 75,000 is added, the pelletization being carried out by means of a high shear mixer, the screening range of the encapsulated pellets is between 800 and 1400 μm, and the dosage unit of each hard gelatin capsule or matrix tablet, of release sustained, 30, 50, 75 or 100 mg of escin.

15 A pharmaceutical formulation ca, containing dry standardized extract of horse chestnut, for the treatment of venous circulatory disorders, venous insufficiency, inflammations, edema including cerebral edema or 5 h incriances, characterized because it is manufactured according to the process of compliance with claims 1 to 14.

16. The pharmaceutical formulation according to claim 15, characterized in that it also contains one or more additional active ingredients that are processed as pellets or contained in the compacted tablet matrix, in combination with the pharmaceutically acceptable carrier and other usual inactive ingredients.

17. The pharmaceutical formulation according to claim 16, characterized in that one or more of the additional active ingredients combined is selected from the group consisting of circulatory drugs, flavonoids, analgesics, diuretics, vitamins and anti-inflammatory agents. 25

18. The pharmaceutical formulation of according to claim 17, characterized in that one or more of the active ingredients is selected from the group consisting of triamterene, thiazides, rutoside, troxerutin esculin, dihydroergotamine, heptaminol, diclofenac, inositol nicotinate or tocopherol.