RU2634258C1 - Filler for capsular inhaler - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: filler contains timodepressin in the form of fine particles of respirable size in the amount of 8.5-11.5 wt % and an inert carrier - inhalation lactose - the rest.

EFFECT: expanded arsenal of drugs for inhalation in the treatment of autoimmune diseases, ensuring drug delivery to the blood in unchanged form.

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Description

The invention relates to the pharmaceutical industry and relates to capsules with a pharmaceutical powder inhalation composition for the treatment of autoimmune diseases.

To achieve a timely effective therapeutic result in the treatment of autoimmune diseases, innovative methods of drug delivery are needed, one of which is the inhalation route of drug administration using specialized devices - inhalers (Zlobin V.N. et al. “Efficiency criteria and basic characteristics of powder inhalers” Vestnik RAMS, 2004, v. 1, p. 35-38).

Recently, there has been growing interest in dry powder inhalers - DPI as a means of inhalation delivery of dosage forms. DPIs are activated by inspiration and do not contain chlorofluorocarbon propellants and, thus, do not destroy the ozone layer (Zlobin V.N. et al. “Performance criteria and basic characteristics of powder inhalers.” Vestnik RAMS, 2004, v. 1, p. 35 -38; Swift DL "Apparatus and method of measuring regional distribution of therapeutic aerosols and comparing delivery sistems." J. Aerosol Sci. 1992; 23 (Suppl. 1): S495-S498).

To achieve the desired “level of deposition” of the drug in the lungs, an aerosol with certain properties is required (in terms of the aerodynamic characteristics of the particles). Medicinal substances for inhalation should have a particle size of 1 to 10 microns to ensure optimal aerodynamic properties (Zlobin V.N. et al. "Performance criteria and basic characteristics of powder inhalers." Vestnik RAMS, 2004, v. 1, p. 35-38; Vanderbist F. at al. "Optimization of dry powder inhaler formulation of nacystelin, a new mucoactive agent" J. Pharm. Pharmacol. 1999; 51: 1229-1234).

The small size of the powder particles creates a very high adhesion between them, forming agglomerates due to the van der Waals interaction. To ensure the dosage of the drug and the distribution of particles of the active substance, fillers are used, which are also micronized substances of a larger size. They play the role of a carrier, since smaller particles of the active substance settle on their surface.

When using DPI as a means for inhalation delivery, it is necessary to pre-dose a mixture of the active substance and the carrier, for example, in the form of capsules or blisters, or place in a larger amount in an inhaler.

EP 0 398 631 describes a method for preparing a mixture for inhalation by grinding a biologically active substance into particles with an average diameter of 5-10 microns, followed by one of two methods: mixing with solid carriers customary in pharmaceutical technology, the average particle diameter being 30 -80 microns or by the manufacture of spherical agglomerates from particles of a biologically active substance (the so-called soft pills), and the latter, when inhaled, again disintegrate into primary particles. A method for producing soft pills is also described in GB Patents GB 1,569,612 and GB 1,520,247. However, upon receipt of soft pills, it is necessary to control the amount of moisture in the biologically active substance.

German patents DE 2535258 and GB 1,520,247 describe a method for filling capsules with soft pills. In vitro experiments have shown that when emptying such capsules using an inhaler, at least 50% of the biologically active substance contained in the capsule is sprayed. However, the percentage of dispersion, established using a four-stage liquid impinger at a flow rate of 60 l / min, is low, and is 13.8-29.5% of the nominal dose.

Patent WO 91/11179 A1 describes the use of lactose, polysaccharides and other compounds as carrier material. According to the description, the particle size of the carrier is 5-1000 microns. The preparation of the powder is carried out by simply mixing the biologically active substance with the material of the carrier. The disadvantage of this method is the large variation in the particle diameter of the carrier.

European patent EP 258356 describes microparticles for inhalation, which are an agglomerate of auxiliary substances, for example, lactose, xylitol and mannitol, and the size of the agglomerate is 30-150 microns. The disadvantage of this method is the relatively complex process for producing a conglomerate of auxiliary substances with a specific particle size.

Another known method (DE 2229981) is to mix a biologically active substance with a water-soluble carrier used in the manufacture of medicines, the size of the carrier being from 80 to 150 microns. The disadvantage of this method is the poor fluidity of the obtained compositions.

German patent DE 4140689 describes an inhalation powder, which consists of a physiologically compatible excipient with an average particle size of about 20 microns and a second component with smaller particles, about 10 microns. Capsules are filled with this mixture and inhaled using a device whose principle of operation is described in German patent DE 3345722. The disadvantage of this method is also the poor fluidity of the obtained composition.

Patent WO2008036003 Al describes a pharmaceutical composition for inhalation comprising a finely dispersed biologically active substance in the form of particles of respirable size and a coarse biologically inert carrier in the form of particles of non-respirable sizes, characterized in that the biologically active substance includes glutaryl histamine with up to 50% content, which can cause unwanted adverse reactions.

Patent RU 2054932 proposes a new inhalation composition for treating bronchial asthma, containing drugs used in bronchial asthma, and sodium benzoate as a diluent. The sodium benzoate content in the composition is from 20 to 99.8%. The resulting mixtures are micronized in a jet mill (the size of 95% of the particles is not more than 10 microns), or the drug base is pre-micronized to 5 microns, and then mixed with sodium benzoate. Dry mixtures are placed in capsules and inhaled through spinnalers or directly in the form of dry powder in special inhalers.

A method of obtaining a dry powder for inhalation is described in patent RU 2221552 B, which involves mixing the ingredients of the composition in a drum mixer. In this manufacturing method, powdered magnesium stearate can be added having an average particle size of from about 1 to 100 microns, in particular from about 5 to 20 microns. The disadvantage of this method is the introduction of an additional excipient, which is undesirable with the inhalation route of administration.

Patent RU 2071317 describes a medicinal powder inhalation preparation containing an active substance and an excipient, characterized in that it contains budesonide or salbutamol with a particle size of 2-15 microns in an amount of at least 90% by weight of the substance, and as an excipient - sodium benzoate or lactose with a particle size of 50-400 microns at least 90% by weight of the filler, while the amount of active substance is 0.5-10.0% of the total weight of the drug.

As a result of studying the process of inhalation of dry drugs using a Cyclohaler type inhaler, it was found that filler particles larger than 400 microns in size from the inhalation device, in most cases, are not removed when inhaled, but remain in the inhaler, which in turn makes it difficult dosing and inhalation of subsequent doses of the drug, particles of the drug from 50-400 microns settle in the oral cavity, while the respirable dose increases.

RU 2140260 proposes a method for mixing a biologically active substance or a mixture thereof with a carrier used in the manufacture of medicines with an average particle size of 200-1000 μm, preferably 300-600 μm, and the particle size of the biologically active substance should be 0.01-10 microns.

All of the above analogues include various biologically active substances and carriers or excipients with different particle sizes. However, the problem of selecting the composition of ingredients, as well as optimizing the particle size of biologically active substances and carriers for powder pharmaceutical inhalation compositions used in the treatment of autoimmune diseases, remains relevant.

For the treatment of autoimmune diseases, RU 2401123 provides a method for treating psoriasis in children with timodepressin by inhalation in doses of 0.5 ml of a 0.025% solution per inhalation. Moreover, for intrabronchial administration, an apparatus is used that converts the drug substance into a finely dispersed, foggy form. However, this invention involves the use of thymodepressin in the form of a solution with the additional use of devices such as "nebulizer". While inhalers (dry powder inhalers) are fundamentally different inhalers, convenient to use due to their small size and portability, unlike nebulizers used at home or in medical institutions.

A technical problem, the solution of which is provided by using the invention, is the expansion of the arsenal of funds for inhalation administration in the treatment of autoimmune diseases that ensure delivery of the drug to the blood unchanged.

The technical result is achieved by the fact that a filler for a capsular inhaler containing thymodepressin in the form of fine particles of respirable size and an inert carrier in the following ratio of ingredients:

thymodepressin - 8.5-11.5%,

inhaled lactose - the rest.

As a biological inert carrier, the excipient contains inhaled lactose.

The proposed filler in capsules for use in the inhaler contains a finely divided biologically active substance in the form of particles of respirable sizes from 1 to 5 microns and a micronized biologically inert carrier of larger sizes from 10 to 150 microns. The pharmaceutical composition for inhalation contains thymodepressin, the mass of which in the composition is from 8.5-11.5%. In this case, thymodepressin is crushed to particles of respirable sizes of 1-5 microns: 100% of the particles by weight less than 5 microns, 97% - less than 3 microns, the mass median aerodynamic diameter of the particles is 1.0-1.5 microns. Then micronized thymodepressin powder is mixed with a biologically inert carrier - inhalation lactose for inhalation with particles ranging in size from 5 to 150 microns: 100% of particles by weight less than 150 microns, 90% - less than 200 microns and not more than 10% - less than 90 microns, mass median particle diameter is about 150 microns. The obtained pharmaceutical powder composition for inhalation with various values of the mass content of thymodepressin (8.5, 10, 11.5%) is filled with white hypromellose capsules No. 3 on a capsule filling machine equipped with a module for dispensing inhalation powders. The average weight of the contents of the capsule should be 0.03 g. The therapeutic use of the capsules is carried out using a powder inhaler (inhaler).

Timodepressin inhibits the reactions of humoral and cellular immunity, reversibly reduces the total number of lymphocytes in the peripheral blood, and causes a proportional decrease in both helper cells and suppressors. The drug inhibits colony formation and the entry of hematopoietic stem precursor cells into the S phase, reduces the number of activation markers on lymphocytes, and inhibits the proliferation of T cells. Timodepressin inhibits the spontaneous production of tumor necrosis factor, enhances the production of interleukin 7, does not affect the production of interleukin. Thymodepressin reduces the likelihood of an acute transplant versus host reaction, and reduces the chronic reaction rate by 90% when the drug is administered to the donor and recipient. The drug also contributes to a more rapid and cooperative release of progenitor cells into the proliferative phase and the restoration of leukopoiesis.

Timodepressin has the following advantages:

- selectively affects the precursors of hematopoiesis in the bone marrow;

- has no side effects inherent in all known immunosuppressants;

- has high stability in the body and the duration of the effect;

- effective in a wide range of therapeutic doses;

- non-toxic in doses many times higher than therapeutic;

- does not accumulate in the body and is completely excreted from the body;

- improves the quality of life of patients by improving their mental state.

Timodepressin is a synthetic peptide drug, used in adults and children from the age of two, is used both in monotherapy and in the complex treatment and prevention of relapse of various autoimmune diseases.

Chemical name: γ-D-glutamyl-D-tryptophan sodium salt

Structural formula

The empirical formula is: C ₁₆ H ₁₈ N ₃ NaO ₇ .

Molecular mass: 355.32.

In appearance - a crystalline powder, white or white with a yellowish tint, with a specific smell. Easily soluble in water, very slightly soluble in ethyl alcohol 95%, practically insoluble in chloroform.

The achievement of the technical result is illustrated by the figures: in Fig. Figure 1 shows the X-ray diffraction spectra of thymodepressin substances before micronization, and Fig. 2 - after micronization, in fig. 3 shows photographs of micronized thymodepressin, in Fig. 4 - photographs of inhaled lactose, in fig. 5 - a mixture of micronized thymodepressin and inhaled lactose.

Example 1

In the proposed pharmaceutical composition for inhalation, the mass content of thymodepressin is 8.5%, while thymodepressin is crushed to particles of respirable sizes from 1 to 5 μm (respirable fraction). Then micronized thymodepressin powder (from 1 to 5 μm) is mixed with a powder of a biologically inert carrier - inhaled lactose, the mass content of which is 91.5%, with particles of non-respirable sizes from 5 to 150 microns (non-respirable fraction). The obtained pharmaceutical composition for inhalation is filled with white hypromellose capsules No. 3, which are used in an inhaler powder inhaler.

Respiratory thymodepressin is obtained by spray drying.

Micronized thymodepressin after spray drying is a stable for a long time X-ray amorphous powder, which was established by X-ray diffraction analysis on an automatic X-ray diffractometer in step scanning mode. The angle range of 2θ is from 4.5 ° to 50 °, the scanning step is Δ2θ = 0.02 °, and the exposure time at the point is 5–10 s (depending on the scattering ability of the sample). We used CuKα radiation, λ = 1.5418 A, which was subsequently decomposed into Kα1 and Kα2 components when processing the spectra.

The X-ray spectrum of the sample of the substance before micronization in Fig. 1 indicates the crystalline state of the sample; the peaks in Fig. 2 correspond to the X-ray amorphous phase of the substance, since a characteristic X-ray amorphous spectrum is observed.

Lactose Inhalation is a special type of lactose intended for use in powder inhalers. In this invention, lactose is used with a particle size of 5 to 150 microns (Fig. 4).

The encapsulation mass is obtained in a universal laboratory unit, into the loading hopper of which the unit is first loaded with lactose inhalation, then thymodepressin. Stirred for 40 minutes at a speed of 150 rpm.

As a result of mixing the micronized substance of thymodepressin and lactose, microparticles of thymodepressin are deposited on the surface of lactose particles.

In fig. Figure 5 shows that spherical thymodepressin microparticles are located on the surface of lactose particles. In this case, lactose acts as a carrier for thymodepressin microparticles, providing the aerodynamics necessary for inhalation.

Example 2

In the proposed pharmaceutical composition for inhalation, the mass content of thymodepressin is 10%, while thymodepressin is micronized to particles of respirable size, then thymodepressin powder is mixed with a coarse powder of a biologically inert carrier - lactose, with a mass content of 90%, with particles of non-respirable sizes. The resulting pharmaceutical composition for inhalation is placed in a container of a metered-dose powder inhaler.

Example 3

In the proposed pharmaceutical composition for inhalation, the mass content of thymodepressin is 11.5%, while thymodepressin is crushed to particles of respirable size, then micronized thymodepressin powder is mixed with a coarse powder of a biologically inert carrier - lactose with a mass content of 88.5%, with particles of non-respirable sizes . The resulting pharmaceutical composition for inhalation is placed in a container of a metered-dose powder inhaler.

The proposed pharmaceutical composition for inhalation, including the biologically active substance thymodepressin with its mass content from 8.5 to 11.5%, allows therapeutically effective amounts of thymodepressin to be introduced into the patient's lungs using metered-dose powder inhalers.

A pharmaceutical composition for inhalation is proposed in which the mass content of fine particles of biologically active substances of respirable size in combination with particles of an inert carrier provide the maximum value of the respirable fraction during inhalation, taking into account the dosage error, while the biologically active substance contains a domestic synthetic peptide that has pronounced immunosuppressive effect - thymodepressin.

The proposed pharmaceutical composition for inhalation has a pronounced pharmacological activity, confirmed by studies on splenocytes and peritoneal macrophages of experimental animals. The effect of the test drug (inhalation powder) upon endotracheal administration on a nonspecific immune response was evaluated by the absorption of latex particles conjugated with fluorescein-5-isothiocyanate by peritoneal macrophages; The effect of the drug on the proliferative activity of rat T- and B-lymphocytes was evaluated. Experimental pathology was modeled by intraperitoneal administration of a pro-inflammatory agent of 3% thioglycolic medium. The test drug under repeated administration (7 days) at doses of 0.24 and 0.72 mg / kg caused a statistically significant decrease in the proliferative activity of T-lymphocytes isolated from the spleen (0.557 ± 0.040 versus 0.746 ± 0.039) as compared with the control. The results of studying the absorption of latex particles conjugated with fluorescein-5-isothiocyanate by peritoneal macrophages showed a statistically significant decrease in the phagocytic activity index of rat peritoneal macrophages after administration of the test drug at doses of 0.24 and 0.72 mg / kg compared to control animals (2, 5 ± 0.10 versus 3.6 ± 0.28). As a result of an experimental study of the pharmacological activity of the drug (powder for inhalation) on splenocytes and peritoneal macrophages, it was shown that the drug under conditions of repeated administration has a statistically significant effect on the phagocytic activity of peritoneal macrophages and the proliferative activity of T lymphocytes isolated from the spleen, which differ in pronounced dose dependence , and can be used to treat autoimmune diseases. Thus, the desired technical result is achieved.

Claims (2)

A filler for a capsule inhaler containing thymodepressin in the form of fine particles of respirable size and an inert carrier in the following ratio of ingredients, wt.%: Thymodepressin 8.5-11.5 Lactose Inhalation rest

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