Extrudates with needle-like acting substances

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to a pharmaceutical composition in the form of the extrudate, containing at least one pharmaceutically active substance in the form of needles, characterised by the fact that the ratio of the particle size of the needle-like active substance to the diameter of strands constitutes at least 1:25.

EFFECT: invention makes it possible to obtain the more homogeneous extrudate.

11 cl, 13 ex, 10 dwg

 

The invention relates to extrudates containing at least one pharmaceutically active substance in the form of needles, and a size ratio of the acicular particles of the pharmaceutically active substance to the strand diameter is at least 1:15, and to the use of these extrudates for the manufacture of medicines.

Masking bitter taste of drugs is an essential prerequisite for the improvement of compliance of medicinal drugs used not only for treatment of a person (particularly in Pediatrics), but also in veterinary medicine. The most simple method of masking the taste of such medicines is the addition of aromatic substances, however, in the case of a very bitter and very soluble in water deistvuya substances can cause problems (Binz, 1996): it is also Known about masking the taste by processing the active ingredient with a hydrophobic filler in the pellets (Kalbe, Hopkins, 1998). Another possibility of masking of taste is the provision of dosage forms coated. The coating materials are, for example, the product Eudragit E (Segee and others, 2004; Lovrecich and others, 1996; Ohta, Buckton, 2004; Petereit, Weisbrod, 1999), shellac (Pearnchob and others, 2003b; Pearnchob and others, 2003a) or cellulose derivatives (AI-Omran and others, 2002; Li and others, 2002; Shirai and others, 1993). The disadvantage of the product Eudragit E is that the masking Vkusa its use is based on ionic interaction between cationic auxiliary agent and an anionic active substances. The disadvantage of shellac is that it is a natural polymer that can have a variable composition. In addition, the coating of the dosage form is a more costly and time consuming process step. Also described solid dispersion hinolincarbonova acids or naphthyridinone acids in insoluble shellac matrix (Cabrera, 2002).

In addition, to mask the taste of medicines used ion exchange resins and inclusion unit. The applicability of ion-exchange resins is limited by the fact that the drug must have ionic properties (Chun, Choi, 2004; Lu and others, 1991; Prompruk and others, 2005). Unit inclusions may be filled only minor quantities of drugs (Sohi and others, 2004).

To mask the taste, you can also use a lipid basis. So, for example, describes a monolithic dosage forms on the basis of solid fat, which additionally contain used to mask the taste of lecithin, sweeteners (Suzuki and others, 2003; Suzuki and others, 2004). The disadvantage of these dosage forms is the need for complete melting of the lipids during their manufacture, which may lead to lack of physical stability. In addition, as a lipophilic binder at low temperature extrusion use solid W�p, distearate of glycerol and stearic acid, and as a coating for masking of taste in this case you should also use Eudragit E (Breitkreutz and others, 2003). Described extrusion of fat below the point of melting for the manufacture of dosage forms, however, the masking of the taste is not the purpose of such extrusion (Reitz, Kleinebudde, 2007; Windbergs and others, 2008).

Masking the taste of drugs with inhibitors of type quinolone-based gyrase is obtained by mixing the active substance with higher fatty acids, and optionally other additives, heating the resulting mixture and implemented after cooling, pelletizing or grinding to a powder (Ahrens and others, 1998). Furthermore, it is known about the production of granules based waxes (Adeyeye, Price, 1991; Adeyeye, Price, 1994; Zhou and others, 1996; Zhou and others, 1998). Relevant studies show that the release of active ingredients depends on the melting point of the used wax and its content in the pellet. The higher the melting point of the wax and its content in the pellet, the slower release the active ingredients. Another possibility of masking of taste consists in the manufacture of the core of cocoa butter or solid fat and the active ingredient, which provide a coating of sodium alginate or carrageenan (see Kirn, Choi, 2004). However, ipoderac full melt, which adversely affects the stability, and, furthermore, the coating represents an additional process step.

It also describes the product Compritol® 888 ATO as forming the matrix component. The pellets are composed of molten product Compritol®, active ingredient and a polysaccharide coating (Mirghani and others, 2000). In accordance with another study of matrix tablets are compressed directly from powder mixture or powdered solid dispersion. Tablets from powdered solid dispersion characterized by more effective masking of the taste, but for their manufacturing it is necessary to completely melt Compritol® (Li and others, 2006). According to another publication (Barthelemy and others, 1999) Compritol® is used for coating pellets and pellets of theophylline. It is also necessary to completely melt the fat.

The use of phospholipids allows you to mask the bitter taste without affecting other flavor characteristics (Katsuragi and others, 1997; Takagi and others, 2001). Furthermore, the addition of phospholipids influences the crystallinity of lipids, which could cause instability (Schubert, 2005). Masking the taste of the powders can be done by layering fine particle excipients on bol�e larger particles of active substance (Wagga and others, 1999).

Also described animal feed, in which by means of extrusion administered active substances (Huber and others, 2003). According to another publication (Petereit and others 2003) by melt extrusion of the medication with the main character and methacrylate polymer is produced extrudates with masked taste, which is ground into a granular or powder, and quickly dissociates dosage form is prepared by mixing both components with medium chain or long-chain fatty acid in the melt. After curing, the product is ground and introduced into a water-soluble matrix (Petereit and others, 2004). Examine medicines controlled release of active substance, which is contained in the lipid matrix of esters of beganovi acid and a hydrophobic diluent (Nabil and others, 1998). In another publication (Thombre, 2004) described designed for Amateur animal drug multiservices form with taste masking additive.

In German dependent form extrudates with improved masking of taste" with the registration number 102007026550.8 (see also the corresponding PCT application PCT/ER/004218) described used in the pharmaceutical extrudates with a diameter of strands of 0.5 mm or less. These extrudates are suitable for masking the taste of medicines.

However, in the case of extrusion of mixtures which contain�asih active substances in the form of needles, suddenly there is a problem, consisting in the fact that if the crystals used medications have a needle form, the implementation of stable and reproducible production process is not possible even under the condition that the length of the needle is much smaller than the diameter of the strands. Production difficulties in the case of processing acicular drugs in principle arise in the implementation of other technological processes. A number of works have shown that the properties of powders made from them, and pills depend on the shape of the particles used active ingredients (Alderborn, Nystrom, 1982; Wong, Pilpel, 1990). So, for example, paracetamol in the acicular form is much less suitability for compression into tablets compared to other crystalline forms, which is evident in the arched configuration of tablets and poor fluidity of the powder (Wang, Zhang, 1995). In the case of ibuprofen with needle-like crystals form also detected very low fluidity and poor cohesive and adhesive properties, and for compacting and tableting the necessary energy consumption increased, and the resulting tablets are the lack of mechanical stability. Agglomeration of crystals or recrystallization in isometric form can significantly improve the suitability of ibuprofen for tableting (Jbilou and other�, 1999; Rasenack, Muller, 2002).

From the technology of glass production by extrusion is known about the streamlining of the acicular particles in the direction of extrusion. In this case, the orientation of the particles is necessary to ensure the anisotropic properties of glasses (Moisescu and others, 1999). During extrusion of the melt viscosity of the softened glass containing acicular particles substantially greater than the viscosity of the softened glass with isometric particles (Yue and others, 1999).

In the case if the particles would have a much smaller size compared with the diameter of the strand (for example, five times), the experts would have to face less serious problems, primarily because they could assume that the particles are oriented in a favorable extrusion parallel direction.

During the implementation of the extrusion process containing acicular active substance mixtures are suddenly confronted with a problem, consisting in the fact that in the extruder in front of the plate with two spinnerets clusters are formed, which block the holes of a die that causes an increase in pressure in front of the plate. In addition, the powder mixture have a low fluidity, in connection with the high speed of the extrusion process to maintain the constancy of their dosing is possible only with great difficulty.

In the case of acicular active ingredients of everything�there are various options satisfactory solution extrusion, however, the variation of the formulation, for example, the variation type of a lipid basis, the addition of other excipients or experiments with a variable content of active substances does not lead to the necessary optimization of the extrusion process. In addition, you can use the plate with two spinnerets with a smooth extension of the inlet channel in the direction of extrusion, however, in the present case, under certain circumstances, this leads to reduced stability of the extrusion process. Significant changes are also extruded through a plate with two spinnerets, especially with smooth internal surfaces. Optimization of extrusion cannot be achieved and by varying the configuration of the worm extruder. Along with this it is possible to vary the process parameters such as extrusion temperature, the dosing rate and the rotational speed of the worm. The extrusion temperature may correspond to a range from a temperature that is 20°C below the melting point of the lipid to the melting point of the lipid. At a very low temperature extrusion is the rapid clogging of nozzles and an extremely rapid rise in pressure extrusion, while too high temperature extrusion of lipids completely melt and come out of the spinnerets in the form of a soft paste.

It turns out that a certain optimization�AI extrusion process can be achieved through the use of nozzles with a larger diameter. Since none of the other changes are crucially allows to optimize the process, carry out the grinding of the powdered active substance (for example, in vostokstrojj mill), accompanied by the grinding of the needle-like crystal structures. It turns out that in the case of small enough particle size of the extrudates can be produced without any problems. In the case of a sufficiently fine grinding of the active substance the extrusion process generally occurs uniformly and reproducibly at a constant pressure even at high content of the drug (up to 50% or even 80%) and diameter of nozzles constituting, for example, 0.3 mm or even 0.2 mm.

In accordance with this present invention relates to:

the extrudates containing at least one pharmaceutically active substance in the form of needles, characterized in that the ratio of the particle size of needle-shaped pharmaceutically active substance to the diameter of the strands is at least 1:15,

- the use of these extrudates for the manufacture of medicines.

The ratio of the particle size of needle-shaped pharmaceutically active substances to the diameter of the strands is usually at least 1:15, preferably at least 1:20, particularly preferably at least 1:25, even more preferably at m�re 1:50, in particular, at least 1:100.

In this case, the particle size should imply the metric d(0,9), which in doubtful cases determined by laser diffractometry. According to the present invention under the metric d(0,9) mean distribution of particle size in terms of volume, according to which 90% of all particles have a size (diameter) of less than or equal to the value of the specified indicator (sometimes, this indicator also denote d(90) or d(v,90), and the notation d(v,90) is used to emphasize the fact that we are talking about the distribution of particle size in terms of volume). Similarly, you should understand the meaning of the indices d(0,5), d(0,1) and so on. Referred to in the present description, the particle sizes determined by laser diffraction using the Mastersizer 2000 instrument (dispersing unit Hydro 2000G) of company Malvern mode and data processing Fraunhofer diffraction, because the values of the refractive index of the particles of active substance were not known. With the proper amount of dissolved sample is subjected to preliminary dispersion with stirring in 2-3 ml of dispersion medium (for example, in an aqueous solution of dioctylsulfosuccinate concentration of 0.1% in the case of praziquantel or in ethanol in the case of mesalazine). Received disper�Oia with stirring (300 rpm) and circulation pump (900 rpm) is introduced into a dispersing unit and perform the measurement. The particle size after processing of the measurement results with the corresponding program expressed as values of the metric d(0,9) (respectively d(0.5) and so on).

Particles of active substances, which are soluble in common solvents (e.g., particles of caffeine), was dry dispersion in a suitable device (e.g., a Scirocco 2000 dry powder feeder) in a stream of air under a pressure of 0.5 bar.

The diameter of the strands proposed in the invention of the extrudates is preferably not more than 0.5 mm, particularly preferably not more than 0.3 mm. you can Usually use the extrudates with a diameter of 0.1 mm, preferably 0.2 mm. In the case of non-cylindrical extrudates maximum distance between the faces or the maximum length of the ellipse is 0.5 mm, preferably 0.3 mm.

The extrudates contain suitable for extrusion framework capable of thermoplastic deformation of the material or mixture of several able to thermoplastic deformation of materials, and optionally other pharmaceutically acceptable excipients and additives.

The framework consists of able to thermoplastic deformation of materials, such as polymers, e.g., polyacrylates or cellulose derivatives, lipids, for example, acylglycerides, surfactant� substances for example, monostearate of glycerol or sodium stearate, macrogol, for example, polyethylene glycol 6000, and sugar, respectively sugar alcohols, e.g. mannitol or xylitol. Preferably use a lipid basis. As lipid bases are suitable, for example, fats, primarily esters of glycerol, preferably glycerol esters of fatty acids with 12-24 carbon atoms. To suitable esters of glycerol include dietary of glycerol, such as glycerinated, triesters of glycerol, such as glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate or glyceryltrinitrate, as well as a complex mixture of monoamino, diapirov and triesters of glycerol, such as glitserillinoleat. Suitable are also triglycerides based on coconut oil, palm oil and/or palm kernel oil (e.g. commercially available solid fats under the trade name Witocan®). In addition, you can use monoglyceride or diglycerides of citric acid and/or lactic acid.

In addition, you can use wax first wax with 30-60 carbon atoms, such as caterpillat.

Such lipids are commercially available products supplied to the market, for example, under the trade names Precirol®, Compritol® and Dynasan®.

Especially preferred�enhance representative of complex diesters of glycerol is for example, glycerinated (for example, the product Compritol® 888 ATO, which contains mainly glycerinated and glycerylmonostearate and glyceryltrinitrate). Particularly preferred representatives of complex triesters of glycerol are, for example, glyceryltrinitrate (in particular, Dynasan® 114), glyceryltrinitrate (in particular, Dynasan® 116) and glyceryltrinitrate (in particular, Dynasan®118).

Fatty bases are preferably powdered products. Many lipids are polymorphic substances which are known in the conditions of temperature and pressure capable of forming a metastable form. When stored in certain conditions may occur a transformation of modifications and the formation of a stable modifications. According to the literature [Reitz, Kleine-budde, 2007; Windbergs and others, 2008] a complex triesters of glycerol (for example, products Dynasan®), the first glyceryltrinitrate (Dynasan 114®), glyceryltrinitrate (e.g. Dynasan® 116) or glyceryltrinitrate (e.g. Dynasan® 118), characterized by a relative stability to the above changes, therefore they are particularly suitable for use as a lipid basis for medicines.

Used as a fatty basis of commercially available substances primarily are often mixtures, for example, Moneglia�ides, diglycerides and/or triglycerides. Compared to such preferred mixtures are homogeneous fatty bases, consisting mainly of only one component: the Drugs produced by the use of such auxiliary substances, have a high storage stability.

To be used the quantity of base (capable of thermoplastic deformation of materials) depends on the quantity of the other ingredients of the extrudates. The base is usually used in an amount of from 15 to 99 wt.%, preferably from 20 to 99 wt.%, particularly preferably from 25 to 80 wt.%, even more preferably from 30 to 70% of the mass.

Used foundations, in particular, lipid basis, typically are characterized by a range of melting points, the lower boundary of which generally corresponds to at least 50°C, preferably at least 60°C.

Proposed in the invention, the extrudates optionally can contain one or more other excipients and additives. To suitable auxiliary substances and additives include means for regulating the flow (preferably colloidal silicon dioxide) at a concentration of from 0.2 to 2 wt.%, lubricant (preferably magnesium stearate or dibehenate calcium) in a concentration of from 0.2 to 5 wt%. and surfactants (pre�respectfully lecithin) in a concentration of from 0.5 to 10 wt%. In addition, you can use antioxidants, such as trouble soothing or stabilizer, which are used in conventional amounts, generally constituting from 0.01 to 0.5 wt.%, preferably from 0.05 to 0.2 wt%. Release of active substance can be controlled, for example, by adding so-called paramesvara. The latter include, for example, sugars, in particular lactose, polyols, particularly mannitol or polyethylene glycols (PEG), preferably PEG PEG 1500 to 10000, particularly preferably PEG PEG 1500 to 6000, in particular, PEG 1500 (Macrogol 1500). Parabrachial used at a concentration of from 5 to 40 wt.%, preferably from 5 to 20 wt%. Another possibility of influencing the release of active ingredient is the addition of support equipment to the collapse. It is also possible to use so-called matter disintegrant, such as copovidone, croscarmellose sodium or crosslinked natrocarbonatite. Disintegrant used at a concentration of from 1 to 15 wt.%, preferably from 3 to 10 wt%. As the relevant alternative, you can use substances that have a solubility in acid and/or release carbon dioxide, such as magnesium carbonate or calcium carbonate. Releasing carbon dioxide substances used in con�the radio from 5 to 15 wt.%, preferably from 5 to 10 wt%.

In addition, the proposed in the invention, the extrudates may contain an antistatic means. In particular, the antistatic agent is recommended in that case, if the electrostatic charges have a negative impact on the extrusion. Electrostatic charges can cause clogging of the holes of the spinnerets, which can be prevented by the addition of antistatic agents. As the antistatic agents can be preferably used a polyethylene glycol, especially preferably from polyethylene glycol PEG 1500 to PEG 6000. For the manifestation antistatic effect of polyethylene glycol should preferably be in a powdery state and to melt in the extrusion process. Accordingly, in the case of use as antistatic polyethylene glycol, a melting range must be sufficiently low so that during the extrusion of the melted polyethylene glycol and not used fat base. In practice, static charges occur when you use not all foundations. Static charges see especially in the case of complex triesters based on glycerol and fatty acids, such as glyceryltrinitrate, glyceryltrinitrate or glyceryltrinitrate.In this regard, in the case of using such frameworks to ensure bezprobl�Noah extrusion to be extruded mixture is recommended to add an antistatic agent. Antistatic agents are used in a concentration equal to at least 5% wt., preferably at least 10 wt%. The concentration of the antistatic agent generally does not exceed 30% of the mass.

As pharmaceutically active substances can be used as active substances of medicines, first of all, the active ingredients that need to hide the unpleasant taste.

According to the invention are used as active substances, which are in the form of needles. The point is that as a rule goes about acicular crystals.

Under the needles, respectively acicular particles, in this case the mean of the particles, the length of which substantially exceeds the diameter, and the ratio of length to diameter is at least more than 3:1, preferably greater than 5:1, particularly preferably greater than 10:1, even more preferably greater than 20:1. Because the needles generally do not have circular cross-sections, in cases of doubt "diameter" means perpendicular to the length of the maximum size.

Because the melting of the active ingredients is missing, the choice of needle-like active substance is in principle not limited by the rigid framework. In connection with the inherent extrudates effect of masking of taste, they can preferably contain the active substance with an unpleasant, e.g. bitter taste.

Acting�e substances can be, for example, representatives of the following groups: antibiotics, anti-protozoan parasites, deworming drugs, agents that stimulate the metabolism, and anti-inflammatory substances.

To the effective substances, obviously, are also acicular salts and solvates.

A specific example of active substance can serve as mesalazin. Mesalazine is an anti-inflammatory drug used against chronic inflammatory intestinal diseases. Mesalazin very sparingly soluble in water, has a melting point of 280°C and a needle-shaped crystal form.

Another example of active substance is crystalline caffeine.

Specific examples of preferred acicular active ingredient is praziquantel, a well-known anthelmintic that is effective against tape worms and shistosoma. Praziquantel is sparingly soluble in water, has a melting point of 139°C and a needle-shaped crystal form. Typically use milled in a rod mill praziquantel with a particle size of 25 μm (measured by laser diffractometry indicator d(0,9) Fig.1).

The introduction of the active substance in a lipophilic matrix allows to ensure that it is sustained release, which is determined by the nature concretely used days�existing substances.

The number used in the extrudates of the active substance depends on its activity and the dosage. According to the invention can be produced extrudates with a high content of active substance as high as 80 wt.%, preferably 70 wt.%, especially preferably 60% by weight. The usual content of active substance, for example, corresponds to the interval from 1 to 80 wt.%, preferably from 5 to 70 wt.%, especially preferably 30 to 60 wt%.

Proposed in the invention, the extrudates are made by mixing the starting materials, i.e., pharmaceutically active (s) substance (s), and optionally used auxiliary substances and additives, and subsequent extrusion of the mixture. The extrusion mixture is preferably carried out at a temperature at which complete melting is able to thermoplastic deformation of the material is missing, which usually takes place in the temperature interval from room temperature, preferably from 40°C to a temperature below the melting point of thermoplastic deformable materials. In practice it usually comes about of the melting point of the corresponding bases. The extrusion is generally carried out at a temperature which is below the lower temperature limit of the melting point basis, especially a fatty basis, not Maine�e than 20°C, preferably not less than 15°C, especially preferably not less than 10°C. the Extrusion is usually carried out at a temperature that does not exceed the lower temperature limit of the melting point of the base and preferably 1°C below her, particularly preferably at 5°C below her. The objective here is to prevent extrusion of the product in the form of a soft paste. The extrusion process should be undertaken with the greatest possible constancy of the temperature of the extruded material. To carry out such extrusion is particularly suitable heated worm extruders, especially twin-screw extruders. The extruded strand preferably has a circular cross-section and above in diameter. The extruded strand can be milled directly on the stage of extrusion with a knife or on a separate stage by gentle grinding in a conventional mill, for example, in a centrifugal mill. The particle size of the obtained product depends on the diameter of the Spinneret used, and the maximum length of chopped strands three times their diameter. The typical particle size is, for example, from 300 to 500 μm, and also, with a smaller diameter Spinneret, from 200 to 500 μm. According to a preferred embodiment, the crushed material further can� be subjected to screening. By sieving to remove the fine fraction.

Repeatedly cited in this description indicating that the production of extrudates is carried out at a temperature below the melting point of the basics that should be understood so that the extrudates are obtained when the above extrusion temperatures, when lacking complete melting of thermoplastic base. Other components, such as active substances, often have a higher melting point. Such extrudates suitable for masking the taste of the ingredients with an unpleasant taste.

Proposed in the invention of the extrudates after gentle crushing, if necessary, can be subjected to further processing in a suitable dosage form. For such additional processing is required in some cases the addition of other excipients. The preferred dosage form according to the invention are tablets, which in some cases may have the form appropriate to their intended use. Other possible dosage forms are pastes, suspensions, sachets, capsules and the like.

Proposed in the invention extrudates, respectively medicines in General suitable for use by humans and animals. They are preferably used�form in the field of animal welfare and animal husbandry for use on agricultural, breeding, zoo, laboratory, experimental and Amateur animals, namely first of all mammals.

To agricultural and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, Indian water Buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, particularly mink, chinchilla and raccoon, birds such as chickens, geese, turkeys, ducks, pigeons and ostriches. Preferred examples of farm animals are cows, sheep, pigs and chickens.

For laboratory and experimental animals include dogs, cats, rabbits and rodents such as mice, rats, Guinea pigs and Golden hamsters.

To Amateur animals include dogs, cats, horses, rabbits, rodents such as Golden hamsters, Guinea pigs and mice, as well as reptiles, amphibians and birds, designed for home and zoo content.

The application of the extrudates is usually carried out directly or in the form of suitable preparations (dosage forms) enterally, especially orally.

Intestinal the application carried out, for example, orally in the form of granulates, tablets, capsules, pastes, suspensions or medicated feed. One possibility oral administration is the so-called top-dressing: this is opporosce, the granulate or a paste, which is added to the feed and give the animals with this food.

Suitable compositions are:

solid compositions such as granules, pellets, tablets, boluses and containing active substances moulded products.

For the manufacture of solid preparations milled extrudates are mixed with suitable bases for medications if necessary, with addition of auxiliary substances, and give the mixture the desired shape.

As for medications, any suitable physiologically compatible solid inert substances. As the last use of inorganic and organic substances. Suitable inorganic substances are, for example, sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicic acid, alumina, precipitated or colloidal silica, and phosphates.

Suitable organic substances are, for example, sugar, cellulose, foodstuffs, feed means, such as milk powder, bone meal, flour from cereal grains, grain meal and starches.

Adjuvants are preservatives, antioxidants and colorants. Suitable auxiliary substances and are required to use the quantity p�such substances are in principle known in the art. Suitable preservative is sorbic acid. As an antioxidant suitable, for example, trouble soothing or stabilizer. As a dye it is possible to use suitable for pharmaceutical purposes organic and inorganic dyes or pigments, such as iron oxide.

Other suitable adjuvants are internal and external lubricants, such as magnesium stearate, stearic acid, talc, bentonites, contributing to the disintegration agents such as starch or crosslinked polyvinylpyrrolidone, binders, such as starch, gelatin or linear polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.

As other auxiliary tools you can use oils such as vegetable oils (e.g., olive oil, soybean oil and sunflower oil) or oils of animal origin such as fish oil. The normal amount of these oils be from 0.5 to 20 wt.%, preferably from 0.5 to 10 wt.%, particularly preferably from 1 to 2% of the mass.

Suspension you can apply orally. To obtain suspensions of crushed extrudates suspended in the liquid base for medications if necessary with the addition of other auxiliary�found substances such as wetting agents, dyes, conducive to the absorption of substances, preservatives, antioxidants and light stabilizers.

As the liquid foundations for medicines you can use homogeneous solvents or solvent mixtures that do not dissolve the respective extrudates. Examples of suitable bases are physiologically compatible solvents, such as water, alcohols, in particular ethanol, butanol, glycerol, propylene glycol and polyethylene glycols, and mixtures thereof.

As wetting agents (dispersants) can be used surfactants. Examples of suitable surfactants are:

nonionic surfactants, for example polyoxyethylated castor oil, polyoxyethylated servicemanual, servicemonitor, glycerylmonostearate, polyoxyethylene and alkylpolyglycoside,

amphoteric surfactants, such as disodium-N-lauryl-β-aminodiphenyl or lecithin,

anionic surfactants, such as nutriceuticals, solitaire aliphatic alcohols, or salt of ester of mono/dialkyldithiophosphoric acid and monoethanolamine,

cationic surfactants, such as �ethyltrimethylammonium.

Other auxiliary substances include, for example:

substances that increase the viscosity and stabilizing the suspension, such as carboxymethylcellulose, methylcellulose and other cellulose derivatives and starch, polyacrylates, alginates, gelatin, gum Arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether with maleic anhydride, polyethylene glycols, waxes, colloidal silicic acid or mixtures of these substances.

Paste-like drugs can be used orally. They differ from the above suspensions and emulsions only higher viscosity.

The active substances can also be used in combination with synergists or other active ingredients.

Examples

In the absence of specific instructions under a percent data imply quantity in percent by weight calculated on the mixture.

I. Comparative example, the extrudate with praziquantel

Prior to extrusion is used as the active ingredient praziquantel (50% wt.) with a particle size of 25 μm (d(0,9) Fig.1) for 15 minutes, mixed at room temperature in a laboratory mixer (40 rpm) with the following adjuvants: used as a fatty basis product Compritol®888-ATO(49% wt.) with glicerinization as osnovnog� component (it contains also monetary and triesters, as well as smaller quantities of esters of fatty acids with 16 to 20 carbon atoms) and used to increase the fluidity of the powder mass is a product of Aerosil® 200 (1% wt.), representing a pyrogenic colloidal silica (also called fumed silica), and the resulting powdery mixture was transferred to a gravimetric feeder of the extruder.

For extrusion in the melt using a unidirectional twin-screw extruder with round forming tool and the conical worm attachments.

In the extrusion process of the above formulation there is a blockage of the die holes, the diameter of which is 0.3 mm (the total number of nozzles in the plate of the extruder is 67), in which, under a constant speed of worms and a constant rate of dispensing, there is a continuous pressure increase (Fig.2). Due to the increase in pressure after the plate with two spinnerets in the implementation of the extrusion with the unground praziquantel significantly increases the speed of exit of the extrudate from the remaining free holes of the spinnerets.

II. Example: the extrudate with finely milled praziquantel

Repeat the experience of the comparative example, using subjected to the double grinding vostokstrojj mill praziquantel (d(075) 1.7 μm, d(0,9) 3.6 μm, see Fig.3).

The process of extras�and milled with praziquantel (50%) when a die with a diameter of 0.3 mm flows uniformly and reproducibly at constant pressure. From consideration of Fig.4 stroke of the extrusion process it is seen that after approximately 12 minutes, the pressure is set at a constant level (about 10 bar), which is much lower compared with extrusion of the formulation with unground with praziquantel (Fig.2), whereby the pressure in 15 minutes is almost up to 40 bar. Extrusion occurs through the die at a uniform rate.

When comparing the extrudates of comparative example I and this example, the following differences are observed. Strong friction when performed according to example I of the extrusion leads to increased surface compaction lipid, clearly visible in the study of the respective extrudates using scanning electron microscopy: the surface is smooth and even. In contrast, the surface of the extrudate with milled praziquantel uneven, particles of praziquantel are directly under the surface and their shape is visible through the thin lipid layer.

III. Comparative example: the extrudate with the unground mesalazina

Extrudates with the unground mesalazina (d(0,5)of 10.7 μm, d(0,9) to 44.0 μm, see Fig.5) is prepared similarly to comparative example I. the Powder mixture consisting of 50 wt%. unground mesalazine, 49 % of the mass. product Compritol® and 1% of the mass. highly dispersed silicon dioxide (product�and Aerosil®), is extruded through a plate with two spinnerets, the diameter of which is 0.3 mm In the extrusion process technological problems arise, similar to comparative example I. the course of the extrusion process (Fig.6) shows that after 10 minutes the pressure set at around 25 bar, however, varies greatly. In this experiment, see also partial clogging of holes of the die, however it does not occur so quickly and on such a scale, as in the case of praziquantel.

IV. Example: the extrudate with the ground mesalazina

As a result of double grinding in vostokstrojj mill get mesalazine with a smaller particle size (d(0,5) of 4.9 μm, d(0.9 a) of 11.9 μm, see Fig.7). The grinding particles of mesalazine accompanied by a significant change of their form.

The use of the ground mesalazine in the extrusion process similar to comparative example III, can significantly streamline this process. As shown in Fig.8, the pressure is set at a constant level (20 bar) after only 5 minutes, and the extrusion takes place through a Spinneret with uniform speed. Thus, the use of the ground mesalazine helps to prevent clogging of holes of the die, and consequently, to optimize the extrusion process.

When comparing the respective extrudates revealed that in the process �strazii is the destruction of a significant part of acicular crystals mesalazine comparative example, while the particles of the ground mesalazine after extrusion retain its original shape and size that is clearly visible, for example, when observed on the heated slide of the extrudate under a light microscope. In contrast, needle-shaped crystals of praziquantel in the extrusion process are not destroyed and being in the extrudate, have its original shape and size.

Based on the above experimental data, the specialists could assume that in the case of large acicular crystals of mesalazine during extrusion should occur more substantial problem than in the case of the smaller acicular crystals of praziquantel. However, the clogging of the holes of the spinnerets and the resulting rapid increase in pressure in the case of mesalazine themselves not so much as in the case of praziquantel, since most of the large acicular crystals of mesalazine is crushed under the action of shear loads provided by the worm of the extruder, in the extrusion process.

V: Comparative example: the extrudate without antistatic

Containing milled praziquantel extrudates prepared analogously to example II. Extruded powder mixture, which contains 50% of the mass. milled praziquantel, 49% of the mass. product Dynasan 116® and 1% of the mass. superfine diox�Yes silicon (product Aerosil®), and Dynasan 116® is a fat basis, which consists of 98% of glyceryltrinitrate. The extrusion is carried out through the plate with two spinnerets with a diameter of 0.3 mm.

In the extrusion process of the formulation specified due to friction lipophilic mass relative to the internal surfaces of the dies on the extrudates are constantly emerging in a strong electric charges, in connection with which after a few minutes the extrudate strongly electrostatically charged from the extruder and adheres to the head with two spinnerets. Due to such electrifying despite the use of milled praziquantel is also blocking individual holes draw plate and the pressure increase after the plate with two spinnerets. Emerging continuously charges recorded during extrusion through electrostatic sensor IZD 10-510 firm SMC installed directly in front of the plate with two spinnerets. For almost two minutes performed according to this comparative example extrusion, electrostatic charge reaches 5 kV (see Fig.9).

VI. Example: the extrudate with an antistatic agent

The extrudates obtained analogously to comparative example V when adding 5 and 10% are used as antistatic polyethylene glycol PEG 1500. Extruded powder mixture containing 50 wt%. milled praziquantel, 44% of the mass. product Dynasan 16®, 5% of the mass. PEG 1500 and 1% of the mass. product Aerosil®, respectively 50% of the mass. milled praziquantel, 39% of the mass. Dynasan 116®, 10% of the mass. PEG 1500 and 1% of the mass. highly dispersed silicon dioxide (product of Aerosil®). The cylinder temperature of the extruder is 60°C, resulting in the melting of the polyethylene glycol in the extrusion process.

In the extrusion process using 5% peg again plugging some holes draw plate, and measured in front of the plate with two spinnerets electrostatic charge in just three minutes is 1 to 2 kV. In contrast, in the case of 10% peg the extrusion process flows uniformly and reproducibly, without clogging the holes of the spinnerets and the occurrence of measurable electrostatic discharge (Fig.9).

Thus, the addition of 10% peg as an antistatic agent to prevent electrostatic charging of the extrudate containing high-purity complex triesters of glycerol, and therefore, significantly optimize the extrusion process.

VII. Comparative example: the extrudate with unmelted antistatic

The extrudates obtained analogously to comparative example VI when adding 10% PEG 6000 as an antistatic agent. Extruded powder mixture containing 50 wt%. milled praziquantel, 39% of the mass. product Dynasan 116®, 10 mass. PEG 6000 and 1% of the mass. highly dispersed silicon dioxide (product of Aerosil®). The initial temperature of the cylinder of the extruder is 60°C, after 8 minutes it is reduced to 55°C and at the end of the extrusion is 52°C. the PEG 6000 melt at a temperature ranging from 55°to 60 ° With, in this connection after the specified reduction temperature, the polyethylene glycol is in an unmelted condition.

Analogously to example VI with 10% PEG 1500 extrusion at the initial stage flows uniformly, without the occurrence of electrostatic charges and clogging the holes of the spinnerets (Fig.10). After the temperature of extrusion is observed electrostatic charging of the extrudates, a few holes clogging of nozzles and the resulting pressure increase after the plate with two spinnerets.

The obtained experimental data show that during extrusion the polyethylene glycol for the manifestation of its inherent anti-static action must be in the molten state.

VIII. Comparative example: the extrudate with unground caffeine

Extrudates with UN-ground caffeine is prepared analogously to comparative example I. the Powder mixture containing 50 wt%. unground caffeine (particle size d(0,9) 1170 µm), 49% of the mass. product Compritol®, 1% of the mass. highly dispersed silicon dioxide (product of Aerosil®), is extruded through� plate with two spinnerets with a diameter of 0.3 mm. During the implementation of the extrusion process problems arise, similar to comparative example I. after 8 minutes due to a complete clogging of the holes of the die pressure increases to such a level that the extrusion process has to terminate.

IX. Example: the extrudate with ground caffeine

To reduce the particle size of caffeine is subjected to the double grinding in vostokstrojj mill.

Use for extrusion subjected to grinding caffeine similarly to example II can greatly streamline the process. After three minutes the pressure is set at a constant level (5 bar), and extrusion flows with uniform velocity through all openings dies. Thus, the use of ground caffeine helps prevent clogging of holes of the die and substantially optimize the extrusion process.

Following the extrudates obtained analogously to the above examples.

H. Examples

70% of the mass. milled praziquantel (d(0,9) of 5.7 μm),

17% of the mass. glyceryltrinitrate (Dynasan® 118),

12% of the mass. PEG 6000,

1% of the mass. highly dispersed silica (Aerosil®).

The diameter of the die holes of 0.3 mm (100% of free holes in the extrusion), the frequency of rotation of the worm 60 rpm, the extrusion temperature of 67°C.

XI. Example

50% of the mass. milled praziquantel (d(0,9) of 5.7 μm),

2% of the mass. glyceryltrinitrate (Dynasan® 118),

20% of the mass. PEG 6000,

1% of the mass. highly dispersed silica (Aerosil®).

The diameter of the die holes (0.2 mm holes 180, 100% free of holes during extrusion), the frequency of rotation of the worm 60 rpm, the extrusion temperature of 67°C.

XII. Example

50% of the mass. milled praziquantel ((1(0,9) of 5.7 μm),

29% of the mass. glyceryltrinitrate(Dnsn®118),

20% of the mass. PEG 6000,

1% of the mass. highly dispersed silica (Aerosil®).

The diameter of the die holes of 0.3 mm (100% of free holes in the extrusion), the frequency of rotation of the worm 60 rpm, the extrusion temperature of 67°C.

XIII. Example

50% of the mass. milled praziquantel (d(0,9) of 5.7 μm),

49% of the mass. glyceryltrinitrate (Dynasan® 118),

1% of the mass. highly dispersed silica (Aerosil®).

The diameter of the die holes of 0.3 mm (3% of the vacant holes in the extrusion), the frequency of rotation of the worm 60 rpm, the extrusion temperature of 67°C.

Biological example: test with cats on the acceptability

Forty cats are partitioned into four groups of ten animals each. Each of the obtained according to examples X-XIII extrudates have ten cats from the respective groups as follows.

To dry food for cats as feeding add the extrudate in such quantity that it sootvetstvenno dosing of 5 mg of praziquantel per kilogram of body weight, and give Kosh�am at the usual time of feeding. Full eating poop reflects 100 percent of the admissibility of the drug.

After a week break, repeat the above experiment, however, use canned cat food (wet). Get a result similar to the test using dry food and which means 100% acceptance of the product.

Drawings

Fig.1 - distribution of unground particles of praziquantel in size (d(0,5) of 6.2 μm, d(0.9 a) of 25.1 μm) measured by laser diffractometry after wet dispersion (instrument Mastersizer 2000, modification 5.54, the company Malvern Instruments, Malvern, UK).

Fig.2 - the process of extrusion of a mixture containing 50% unground praziquantel, 49% Compritol® and 1% of highly dispersed silicon dioxide (Aerosil®), plate with two spinnerets with a diameter of 0.3 mm.

Fig.3 - distribution of particles at twice the rate of crushed praziquantel size (d(0.5) is 1.7 μm, d(0,9) 3.6 μm) measured by laser diffractometry after wet dispersion (instrument Mastersizer 20007 modification 5.54, the company Malvern Instruments, Malvern, UK).

Fig.4 - the process of extrusion of a mixture comprising 50% of the milled praziquantel, 49% Compritol® and 1% of highly dispersed silicon dioxide (Aerosil®), plate with two spinnerets with a diameter of 0.3 mm.

Fig.5 - distribution of particles of unground mesalazine size (d(0,5) of 10.7 μm, d(0,9) to 44.0 μm) measured m�by the method of laser diffraction after wet dispersion (instrument Mastersizer 2000, modification 5.54, the company Malvern Instruments, Malvern, UK).

Fig.6 - the process of extrusion of a mixture containing 50% of unground mesalazine, 49% Compritol® and 1% of highly dispersed silicon dioxide (Aerosil®), plate with two spinnerets with a diameter of 0.3 mm.

Fig.7 - distribution of particles crushed twice mesalazine size (d(0,5) of 4.9 μm, d(0.9 a) of 11.9 μm) measured by laser diffractometry after wet dispersion (instrument Mastersizer 2000, modification 5.54, the company Malvern Instruments, Malvern, UK).

Fig.8 - the course of the extrusion process, the mixture containing 50% of the ground mesalazine, 49% Compritol®and 1% of highly dispersed silicon dioxide (Aerosil®), plate with two spinnerets with a diameter of 0.3 mm.

Fig.9 - electrostatic charge in front of the plate with two spinnerets during the extrusion process (the content of PEG 1500 0, 5, and 10%).

Fig.10 - the process of extrusion of a mixture comprising 50% of the milled praziquantel, 39% Dynasan 116®, 10% PEG 6000 and 1% of highly dispersed silicon dioxide (Aerosil®).

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1. Pharmaceutical composition in the form of an extrudate containing at least one pharmaceutically active substance in the form of needles, characterized in that the ratio of the particle size of needle-shaped pharmaceutically active substance to the diameter of the strands is at least 1:25.

2. Pharmaceutical composition in the form of an extrudate according to claim 1, wherein the diameter of the strands is 0.5 mm or less.

3. Pharmaceutical composition in the form of an extrudate according to claim 1, containing as auxiliary substances of a lipid basis.

4. Pharmaceutical composition in the form of an extrudate according to claim 3, containing as lipid basis the ester of glycerol and fatty acids with 12-24 carbon atoms.
5 Pharmaceutical composition in the form of an extrudate according to claim 3, containing as the basics of complex lipid diester of glycerin.

6. Pharmaceutical composition in the form of an extrudate according to claim 5, containing as lipid about�new glycerinated.

7. Pharmaceutical composition in the form of an extrudate according to claim 3, containing as lipid fundamentals of complex triavir glycerin.

8. Pharmaceutical composition in the form of an extrudate according to claim 7, containing as a lipid basis glyceryltrinitrate, glyceryltrinitrate or glyceryltrinitrate.

9. Pharmaceutical composition in the form of an extrudate according to claim 8, containing as lipid basics glyceryltrinitrate.

10. Pharmaceutical composition in the form of an extrudate according to claim 1, further comprising an antistatic agent, in particular, polyethylene glycol

11. Pharmaceutical composition in the form of an extrudate according to one of claims.1-12, extruded below the lower boundary of the melting point of the contained framework.



 

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2 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for producing a tablet by (i) compressing a powder mixture in a mould plate of one device for producing a tabletted form with the powder mixture comprising a pharmaceutically active substance and a fusible binding agent, and (ii) exposing the above tabletted form to radio-frequency radiation generated by the above device over a period of time adequate to soften or melt the binding agent inside the above tabletted form to produce a tablet. Oral absorption of the produced tablet placed on the tongue takes less than approximately 30 s.

EFFECT: more effective method for producing the tablet by (i) compression.

18 cl, 14 dwg, 7 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and concerns a stable composition of nanostructured Sildenafil inhibiting cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDEV) containing a nanostructured Sildenafil base or its pharmaceutically acceptable salts having an average particle size of less than approximately 500nm, a stabilising agent, wherein the composition is prepared in a microfluidics-based continuous-flow tank reactor, and the composition possesses a semi-amorphous structure. The group of inventions also concerns a method for preparing the composition of nanostructured Sildenafil; using the above composition for preparing the pharmaceutical composition for treating male or female sexual dysfunction and pulmonary arterial hypertension.

EFFECT: group of inventions provides the improved solubility of the composition.

8 cl, 11 ex, 14 dwg

FIELD: medicine.

SUBSTANCE: invention represents a drug preparation for Parkinson disease containing micronised L-DOPA (3-hydroxy-L-tyrosine) as an active ingredient, which represent stable particles containing poly(lactic-co-glycolic acid 50/50 (PLGA 50/50), or poly(lactic-co-glycolic acid 75/25 (PLGA 75/25), or poly(lactic-co-glycolic acid 50/50 with carboxyl group (PLGA-COOH 50/50), or lactic acid polymer (PLA) in an amount of 75.0÷79.0 wt %, D-mannitol in an amount of 7.5÷8.0 wt %, as well as either polyvinyl alcohol (PVA) or Tween 80.

EFFECT: treating Parkinson disease more effectively.

2 cl, 4 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: agent contains a nanocomposite representing carbon-containing nanoparticles coated with organic alkyl functional groups presenting radicals -C4H9, -C6H11, -C8H15, -C10H21, -C16H33, -C18H35. The above groups are applied by covalent modification with using diazonium salts of the general formula XC6H4N2+ -Y, wherein X is an alkyl radical C4H9, -C6H11, -C8H15, -C10H21, -C16H33 or C18H35, Y-anion -HSO4, -Cl, -BF4 or -OTs.

EFFECT: reducing blood plasma cholesterol and triglycerides effectively.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: method of producing dry earthworm powder includes: contacting live earthworms with chloride(s) of at least one metal selected from a group consisting of potassium, sodium, magnesium and calcium; subsequently contacting the live earthworms with powder of a hydroxycarboxylic acid(s) (or aqueous solution) and diluting the obtained mixture with water to adjust pH to 2-5, followed by leaving the live earthworms to stand for 3-180 minutes, washing the live earthworms with water, grinding the washed live earthworms and freeze-drying the obtained ground product (version).

EFFECT: method enables to obtain powder with high enzymatic activity.

6 cl, 8 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: highly dispersive pharmaceutical composition contains from 5 to 100 mg of budesonide per 1 g of β-glycine. Composition is characterised by bulk density 0.008-0.035 g/cm3 and consists of porous spherical agglomerates with diameter to 50 mcm and separate fragments, formed in the process of destruction of agglomerates, which represent complex of joined into perforated layers separate particles. Composition is obtained by method, based on dispersing into tank with liquid nitrogen solutions of initial substances in mixed solvent tetrahydrofurane-water, in which concentration of tetrahydrofurane constitutes 20-25 wt %, solvents are removed from obtained by dispersion mixture of solid phases in dry nitrogen flow under pressure 100 Pa until pressure drop less than 2 Pa by step-by-step temperature increase in the interval from -196°C to -5°C to decompose clathrate hydrate formed in the system tetrahydrofurane-water and to remove components of used mixture of solvents by sublimation, then from -5°C to +30°C to remove residual moisture, with application of initial substances budesonide and α-glycine in mixed solvent tetrahydrofurane-water with ratio budesonide from 0.25 to 0.9 mg/g of solvent, α-glycine from 8 to 50 mg/g of solvent.

EFFECT: improved method of composition obtaining.

2 cl, 5 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: as medications composition includes beclomethazone dipropionate and salbutamol, with beta-glycine serving as carrier. Composition is obtained by dispersing solutions of initial medications in mixed solvent into tank with liquid nitrogen with further removal of solvents from obtained by dispersion mixture solid phases in dry nitrogen flow under pressure 600±20 mtorr to pressure drop less than 8 mtorr with stopping nitrogen supply by step-by-step increase of temperature: in the interval from -196°C to -15°C, then from -15°C to +30°C. As initial substances used are: beclomethazone dipropionate 1.9-5.1 wt %, salbutamol 1.9-10.2 wt %, alpha-glycin to 100%. Composition of mixed solvent includes tetrahydrofurane 5-15 wt %, tert-butyl alcohol 15-5 wt %, water 77-80 wt %.

EFFECT: invention provides obtaining highly dispersed pharmaceutical composition of salbutamol and beclomethazone dipropionate.

2 cl, 10 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition containing N-[3-chlor-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulphonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine or its pharmaceutically acceptable salt as an active pharmaceutical ingredient in an amount of more than 60 wt % to less than 85 wt % as related to total weight of the composition. The active pharmaceutical ingredient is characterised by a wetting angle of less than 55°.

EFFECT: method for preparing the pharmaceutical composition involves the stage of grinding or milling the above pharmaceutical ingredient in the presence of one or more excipients.

7 cl, 7 dwg, 5 tbl, 6 ex

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