Composition for delivering stable injectable liquids and method for delivery

FIELD: medicine.

SUBSTANCE: the present innovation deals with delivering a stable biologically active compound for a subject including glass particles that contain the mentioned biologically active compound at their diameter ranged 0.1-100 mcm and suspended in liquid that includes, at least, one biocompatible perfluorocarbon where these mentioned particles are not dissolved. The innovation enables to create completely stable compositions being ready for injections.

EFFECT: higher efficiency.

11 cl, 2 dwg, 11 ex


Prerequisites to the creation of inventions

Vaccine or ready for injection of drugs in solution are, in fact, unstable and must be cooled. The pharmaceutical industry usually solves the problem related to the instability of drugs by drying medicines by lyophilization. This method is costly, inconvenient and in fact dangerous, as reconstitution of dried medicinal drugs can lead to erroneous doses or contamination of solutions. Over the last 100 years, attempts were made to develop a reliable, stable, ready for injection of the liquid composition, but efforts were not crowned with success. In fact, only low molecular weight drugs can exist in aqueous solutions within the appropriate retention period.

This problem is particularly acute in the field of vaccine production. It has been estimated that in this world by the year 2005 must be entered 3.6 billion doses of vaccines. The world health organization (WHO) stated that the standard form of the vaccine, which must be cooled all the time, it is not possible to apply in practice ("Revolutionizing Immunizations". Jodar L., Aguado, T., Lloyd J. and Lambert P-H. Genetic Engineering News Feb. 15.1998). Currently, in developed countries use the network holodilny is s, forming a "cooling chain", which is extruded from producing vaccines enterprises to the provincial cities. The cost of the cooling chain for the vaccine industry and non-governmental health organizations, conducting immunization campaigns of the population are enormous. WHO was established that the true costs with maintenance of the cooling chain is over 200 million dollars annually. In addition, immunization campaigns may be conducted only for those people that are in the vicinity of the last section of the cooling chain.

Of the vaccination of the population require trained medical personnel in order to ensure the correct dose and the absence of its destruction. The need to rebuild some vaccines, such as measles, yellow fever and BCG, in this area also represents a serious problem. The problem should be solved very accurately to ensure proper dosing and, in addition, do not make possible source of contamination, which often leads to adverse clinical consequences. In addition, often require the introduction of more than one vaccine during the campaign and this may require multiple injections, as a separate mixture or multivalent vaccines could the t to be unavailable due to chemical incompatibility of some of the components. WHO has highlighted the mentioned problems with the active support of research aimed at creating a stable of next generation vaccines that do not require cooling (Pre-Filled Monodose Injection Devices: A safety standard for new vaccines, or a revolution in the delivery of immunizations?" Lloyd J. and M.T. Aguado WHO publication. May. 1998. "General policy issues: injectable solid vaccines: a role in future immunization?" M.T. Aguado, L. Jodar, Lloyd J., Lambert P.H. WHO publication No A59781).

The ideal solution to this problem is to have a completely stable, ready for injection compositions. Such stable vaccines can be packaged in a device for introducing or for campaigns of mass immunization, can be transported in large quantities and is entered via a needleless injector. Percutaneous delivery of dry, solid particles using a needleless gasinjections system was described in a publication (Sarphie DF, Burkoth TL. Method for providing dense particle compositions for use in the transdermal particle delivery. International publication PCT Pub No. WO 9748485 (1996)) and the transdermal vaccination with dry DNA vaccines is apparently very effective ("PowderJects Hepatitis B DNA Vaccine First To Successfully Elicit Protective Immune Response In Humans" at (1998)).

Supersonic shock wave of helium gas, which is used to bring it into working condition such powder injectors, has limited power and cannot deliver the fine particle dose intramuscularly. This is sredstv is e, that low-molecular particles cannot acquire the appropriate driving force for deep penetration. At that time, as intradermal delivery of DNA vaccines deposited on particles of colloidal gold, is sufficient to achieve the immunogenicity of common vaccines, complemented insoluble aluminum salts or calcium cause unacceptable skin irritation. They should be administered intramuscularly. For the introduction of such vaccines require a flexible system, capable of providing a wide range of depths delivery, intradermal to deep tissue, similar to the delivery system, achieved by using a needle and syringe. For the campaign of mass vaccination of the population problem was solved by developing a liquid needleless injector, capable of accelerating the flow is narrow (˜0.15 mm diameter) liquid stream using a pressure of about 3000 pounds per square inch, in the form of "liquid nails". This device allows you to deliver the dose painlessly through the skin deep into the subcutaneous tissue or muscle tissue by punching tiny holes through the epidermis. A large driving force is given to the liquid jet provides a deep penetration. Still injectable drugs and vaccines were based on the water, but because of the problems of instability discussed above, the region is mobilnyh in water products, available for this technique is very limited.

It is now known that a wide area of bioactive molecules can be stabilized by drying in a glassy sugar (Roser B. "Protection of proteins and the like, the United Kingdom patent No. 2187191. Roser B. and Colaco C. "Stabilization of biological macromolecular substances and other organic compounds", international PCT publication Pub No. WO 91/18091. Roser B. and Sen, S. "New stabilizing glasses". PCT patent application No. 9805699.7. 1998). Such dry, stable active substance is not exposed to adverse environments such as high temperature and ionizing radiation.

The mechanism underlying the significant stabilization of the molecules of sugars, is stekloobrazovanie. Because the sugar solution containing the active molecule, is dried, it can either crystallize when the limit is reached, the solubility of sugar, or may form a supersaturated syrup. Property of sugar to prevent crystallization is important for a good stabilizer. Suitable sugar is trehalose (Green JL. & Angel CA. Phase relations and vitrification in sacchsride water solutions and the trehalose anomaly J.Phys.Chem. 93, 2880-2882 (1989)), but it is not the only sugar. In addition, drying gradually leads to hardening of the syrup, which reaches a glassy state at low content of residual water. Quietly Akti is some molecules move from the liquid aqueous solution in solid solution in dry glassy sugar. Chemical diffusion is negligible in a glassy sugar and therefore a chemical reaction, in essence, stop. Because denaturation is a chemical change, it may not happen in a glassy sugar, and the molecules are stabilized. In this form of the molecule may remain unchanged if another condition. This condition is the second important property of a good stabilizer, and it should be inert and non-reactive. Many glassy substance, it is impossible to obtain, because they react with the product during storage. Obvious problems are found with the reducing sugars that can form a glassy sugar with favorable physical properties, but then their aldehyde groups attack of the amino group on the products, including the typical reaction of Maillard. This fact is the main reason that many dried by lyophilization of pharmaceutical preparations require storage under refrigeration. Non-reactive sugar give stable products that do not require cooling at all.

Biomolecules immobilized in a glassy sugar, are also stable in non-aqueous industrial solvents in which they themselves and the sugar has dissolved (Cleland JL. and Jones AJS. "Excipient stabilization of poypeptides treated with organic solvents" U.S. patent No. 5589167 (1994)). Because glassy sugar serves as an impermeable barrier in prestorage liquid biomolecules in solid solution in such Sahara protected from chemical reactivity of the solvent, and the environment. In that case, if the liquid itself is stable, sensitive products suspended in the vitreous particles form a stable two-phase, liquid composition. Industrial solvents of the type described by Cleland and Jones (1994), have limited application in technology. Substitution biocompatible non-aqueous liquid should lead to the creation of a stable liquid compositions containing even the most unstable of medicines, vaccines and diagnostics.

The first production of stable non-aqueous liquids, for use in the delivery of drugs and vaccines (B.J.Roser and S.D.Sen "Stable particle in liquid formulations". PCT patent application No. GB98/00817), belonged to the compositions of the powders stabilizing the vitreous substances containing the active substance suspended in injectable oils, such as sesame, peanut or soybean oil, or esters, such as etiloleat. Suspended particles of glassy sugar are extremely hydrophilic nature, while oils are hydrophobic. Because of the strong trends hydrofilm the th and hydrophobic phases for the separation of particles of glassy sugar are eager to join. To stabilize this type of suspension "water in oil"often requires the use of soluble oil surfactants dissolved in the continuous oil phase.

These surfactants with low products HLB (hydrophilic/lipophilic balance) gather at the interface between a hydrophilic particles and oil and cover their amphiphilic layer, which is more compatible with the continuous oil phase. Because each particle glassy sugar is separated from its neighbors by a dry oil, no chemical interaction between the particles does not occur. Therefore, there may be several different populations of particles, and each contains an excellent potentially interacting molecule, in the same oil drug without their interaction with each other. Complex multivalent vaccines can be obtained in the same way.

However, it was subsequently found that this method has certain shortcomings that hinder the adoption of universal solution. These shortcomings include the inevitable sedimentation of the suspended particles, which have a density of about 1.5 g/cm3in less dense oily solvent. Applicants recognize the existence of such problems and try to solve it by reducing the size of the cha the TIC to a size below 1 micron in diameter, so that the particles remained suspended by thermodynamic forces such as Brownian motion. The requirement of particle size, which should be below 1 micron in diameter, is a disadvantage of the proposed compositions. The receipt of such powders with small particle is in no way an easy task. Improved models of spray dryers give you the opportunity to get these powders, however, the small particle size will prevent the use of a cyclone-type collectors, resulting in the need for the filter system to return the product.

Theoretically, reduction of particle size to sub-micron can be achieved after the particles suspended in the oil by means of the apparatus for microhomogeneous under high pressure, such as microfluidizer (Constant Systems Inc.). This procedure involves the inclusion of additional steps in the way, and applicants have found that it is not very effective for the destruction of the microspheres glassy sugar, dried by spraying, which have extremely high mechanical strength due to their spherical shape. It involves the execution of multiple transits through the apparatus. And even after this procedure, larger particles remain intact, and their removal is required what is the next stage of filtration or sedimentation. In addition, the high viscosity of suspensions in normal oily solvents complicates their selection into the syringe, and to introduce them slowly. This circumstance prevents the rapid passage flows through the fine holes such that take place in the liquid system needleless injector.

In addition, it was found that the suspended oil particles, especially those that contain a surfactant with low products HLB, subsequently it is difficult to extract in the aquatic environment, because, surprisingly, they hold firmly bound, water-repellent coating of oil around the particles, even after washing in aqueous buffer. In order that the particles have left the oil phase and transferred to the aqueous phase, requires a very vigorous shaking and mixing or adding more water-soluble detergent (this time with a high products HLB). This can create big problems, as the particle size decreases. The end result is rather polluted mixed emulsion than two separated phases. In the body of this emulsion may lead to a slow and unpredictable release of the active substance rather than will happen required a rapid and predictable delivery. Extraction in vitro in the aquatic environment leads to the spread of oil on top of water f is s, containing the dissolved active substance. This result may be unacceptable for some usages in vitro, such as diagnostic kits or systems for automatic analysis. In the end, the most natural, FDA-approved oils, which can clinically apply, subject to photodegradation, oxidation or other types of deterioration and require careful storage in the dark at relatively low temperatures. In addition, they are not completely chemically inert so that they can be slow to interact with suspended particles.

United pharmaceutical company investigated the use of powders of water-soluble substances in a striking new, non-aqueous perfluorocarbon liquids (Kirkland WD Composition and method for delivering active agents, U.S. Patent No. 5770181 (1995)). This patent primarily relates to the functions of the PFC as oral, increasing contrast agents for diagnostic imaging of the intestine. Water-soluble powder, which was used in this case, was added in order to improve appetite or increase the effect of contrast PFC in the gastrointestinal tract. However, Kirkland suggested that these liquids can also be used for drug delivery, although in the patent examples were not provided. In particular, in the patent shows only sokhranenia commercially available powders. Currently, applicants found that to obtain the most stable two-phase PFC liquid compositions for oral and parenteral delivery, can be obtained fragile active particles stable in the glassy microspheres sugar. This fact greatly enhances the application of the patent Kirkland to parenteral delivery of drugs and vaccines in the form ready for injection compositions, which do not require cooling of any type. Of particular importance is the discovery of the fact that qualities such as low viscosity, high density and low surface tension PFC, contribute to the fact that the data is stable suspension can be delivered with the help of automatic devices such as liquid needleless injectors. This fact leads to two possible additional applications in addition to those listed, namely the campaign for mass immunization and also Samovodene.

Perfluorocarbons PFC) are new, extremely stable liquids obtained by complete fluorination of certain organic compounds. They cannot be classified as hydrophilic or hydrophobic, since they are, in fact, not mixed with any oil or water or Lyubimkin solvent, whether it is polar or nonpolar, to the exclusion of other PFC (Rewiewed in Krafft MP & Riess JG. "Highly fluorinated amphiphiles and colloidal systems, and their applications in the biomedical field. A contribution. "Biochimie, 80, 489-514, 1998). In addition, they do not participate in hydrophobic interactions with oils or in hydrophilic interactions with water or hydrophilic materials. As a result, as can be seen, a rough separation of the phases, wherein the hydrophilic particles firmly together in the oil, does not occur in the PFC. To obtain stable suspensions do not require surfactants, but ftoruglevodorodnye (FHC) surfactant available (Krafft & Riess, 1998), and they are active at very low concentrations in the PFC liquids. At these very low concentrations FHC surfactants contribute to the formation of true monodisperse systems of certain particles, which tend to aggregate in their absence. PFC liquids are themselves fully chemically non-reactive, and the types of such liquids with low molecular weight does not accumulate in the body, but, being volatile, eventually evaporate during breathing.

Because they are excellent solvents for gas, PFC already used in large quantities in very special cases of clinical application. Their ability to exchange dioxide ug is erode on dissolved oxygen were better than the capacity of the hemoglobin. First results were presented at the "bloodless rats" researcher R.P.Geyer in 1968 (Geyer RP, Monroe RG & Taylor K. "Survival of rats totally perfused with perfluorocarbon-detergent preparation." In: Organ Perfusion and Preservation, J.V.Norman, J.Folkman, L.E.Hardison, L.E.Riodolf and F.J.Veith eds. Appleton-Century-Crofts, New York. 85-95 (1968)). Currently perforative, in the form of a PFC emulsion in the water and under the trade name OxygentTM(Alliance Pharmaceutical Corp.), used instead of blood for transfusion in certain surgical procedures. In addition, the PFC is used as liquids for inhalation into the lungs to treat respiratory distress syndrome in premature infants.

It was found that their high density in combination with chemical inertness is a very valuable quality. Performanance under the trade name VitreonTM(Vitrophage Inc.) used to prevent collapse of the eye capsule during the operation and to shift debonded of the retina. In addition, PFC used as contrast media for imaging method for nuclear magnetic resonance imaging (MRI), and to this end, researchers have shown that hydrophilic powders can be suspended in them in order to improve the visualization or to make them more enjoyable (Kirkland W.D. "Composition and method for delivering active agents" US patent No. 5770181, 1998). This patent also suggests the COI is lesofat PFC as a continuous phase for the delivery of bulk water soluble drugs. As the number of parenteral drugs, which are stable in the form of dry powders at room temperature, is limited, this patent does not apply to most injectable drugs. However, the use of stabilization of the drug in powder glassy sugars in the form of microspheres, as described by researchers Roser and Garcia de Castro (1998), as well as injectable PFC makes this method applicable to virtually all parenteral drugs and vaccines.

The invention relates to compositions for the delivery of stable, biologically active compounds to a subject, comprising particles of glass containing the specified biologically active compound and characterized by the fact that the particles suspended in the liquid, which includes at least one perfluorocarbons, in which these particles do not dissolve.

The glass preferably includes sugar glass, metacarbonate glass and/or phosphate glass.

Thus the invention presents a composition for delivery of a medicinal product of a two-phase system with PFC as a continuous phase containing discrete phase glass in suspension, as agents for drug delivery.

A brief description of the invention

p> The present invention involves the use of a two-phase system with PFC in the form of a continuous phase containing discrete phase glassy substances in suspension, as preparations for the delivery of drugs. Drugs based on perfluorocarbons, have a major advantage in that various PFC can be mixed with the formation of finite mixtures with densities, ranging from about 1.5 to 2.5 g/cm3. This approach makes it possible to obtain particles with densities corresponding to the suspension liquid so that the particles do not pop up to the surface or do not fall on the bottom of the container, but remained in the form of a stable suspension. Therefore, the particles must not be of submicron size, as required for products based on oil, to prevent sedimentation, but they can greatly vary in size. The ultimate particle size is determined only by what is used or needleless injection may contain a particle size in the range from 0.1 to 100 micrometers, or preferably from 1 to 10 micrometers. This approach would greatly simplify the production method of the particles and to avoid the need to obtain particles with very small size by grinding. Particles can be obtained from the use of conventional spray drying or drying by lyophilization followed by a simple drying or wet grinding. When you want a high content of solid particles in suspension, it is desirable that the particles were spherical in shape. Particles of irregular shape are much higher tendency to "link" together, impeding the free flow, while the spherical particles have a specific "lubricating ability, making it possible to achieve a solids content of over 20%. Preferably the solids content is from 1% to 40%, or more preferably from 10% to 15%. Such particles can easily be obtained by spray drying, drying by lyophilization and hardening of the emulsion. For powders suspended if they received accordingly, does not require surfactants that form a stable suspension in which particles of sugar glass dissolves almost instantly when shaken with water. If minor aggregation to perceive as a problem, then a small amount of FHC surfactants, as described by Krafft and Riess (1998), can be added to the PFC liquid before or after adding a stable powder. In case of using the surfactant, it is preferably contained in a concentration of from 0.01 wt.% up to 10 wt.%, optimally probably about 1%. Like PFC, these FHCs, in fact, are extremely inert and non-reactive is. Thus, the solvation of particles and chemical reactions between the suspended particles and the PFC phase does not occur. As the particles of a suitable glass and PFC liquid is stable from an environmental point of view, the degradation due to light, high temperatures, oxygen, etc. does not occur. They have little in vivo and in vitro toxicity, and they have been widely tested and approved by regulatory authorities for the introduction of animals and humans in large quantities to replenish blood loss. It was noted that at the time, as high molecular weight PFC accumulate in the liver, low molecular weight samples used in accordance with the present invention, are eliminated from the body during breathing.

Low surface tension and low viscosity of these PFC enable them to flow very easily through narrow openings, which can be needle for subcutaneous injection, automatic systems or liquid needleless injectors. PFC are excellent insulators, and so it is easy to obtain monodisperse suspension of particles, bearing on the surface of the same small electrostatic charge. They are dry and fully nephroscopes liquids. The degree of dryness of the suspended powders is supported by the low water content, preventing the dissolution or degradation of enabled what's active particles. These compounds do not possess the properties of solvents, which makes them ideal for suspension of hydrophilic or hydrophobic particles, and this means that the resulting suspensions are compatible, in fact, any materials used in containers or devices for delivery. Such qualities compounds of the opposite qualities of products based on oil, which can cause serious damage to the syringe, for example, when the swelling of the rubber seals on the pistons. PFC can be obtained with densities, the elasticities of steam and leucostoma in the area specified in the table (table 1). High density connections lead to subsidence in the most ordinary buffers, allowing easy separation from the obtained particles that are dissolved in the aqueous phase above. This fact facilitates the use of these compounds in vitro, for example for diagnostic purposes.

Detailed description of the invention

Table 1

Properties of some PFC
PERFLUORO-Mol. WeightDensity (kg/l)Viscosity (MPa·)Surface tension mn/mWater vapor (mbar)
hexane3381,6820,656 11,1294
the phenanthrene6242,0328,419<1

The use of PFC as solvents for the delivery of pharmacological agents or bioactive agents has been previously proposed Kirkland (1995). This patent was given as an example in regard, indeed, the only stable commercially available aromatic or effervescent powders and the like. It contains no examples of any stable bioactive drugs, such as vaccines or pharmaceuticals. In addition, it is not considered the possibility of obtaining injectable (parenteral) of the drug using PFC as a solvent for suspension of active particles. In order to achieve a stable composition containing essentially unstable biomolecules, with a long shelf life, using PFC as the nonaqueous solvent, the particles receive, preferably, with content stekloobrazuyuschego agent capable of stabilizing the active substance. Specified AG the HT can be from a number of sugars, including trehalose, lactic, palatinit etc. as described in international PCT publication No. WO 91/18091, or more preferably more efficient sugar alcohols consisting of monosaccharides, or flowed forming agents described in the patent application in the UK No. 9820689.9.

In order that the particles do not pop up in the dense phase PFC, it is advisable to include in the regulatory particle density agent, such as inorganic salt. This agent may be a soluble salt, such as sodium or potassium chloride or sulfate or, more preferably, insoluble material such as barium sulfate, calcium phosphate, titanium dioxide or aluminum hydroxide. Insoluble, non-toxic materials are preferred, since the release of large quantities of ionic salts in the body can cause considerable local pain and irritation. In some cases, such as drugs, vaccines, insoluble materials may be part of the active drug as adjuvant. Control density may be in a solid solution particle of sugar glass or insoluble, granular material in suspension in the sugar glass. Particles of sugar glass, properly prepared, have a density that corresponds roughly to the liquid PFC, have neutral buoyancy, and don't swim n the surface, do not settle down, but remain in stable suspension without formation of lumps.

As PFC liquids are good electrical insulators with a value of specific resistance is usually higher than 1013Ohm·sm, small charges on the surface of suspended particles can have a significant impact on the stability of the suspension. In order to prevent suspended particles from aggregation due to weak forces with short-range, they are made with a filler, such as lysine or aspartic acid, capable of transmitting weak residual electrostatic charge of dry particles. In the aggregation of particles is prevented by the repulsion of their charge, similar to what occurs in a stable colloids. Alternatively, a small amount of FHC surface-active substances, such as perpendicula acid, can be dissolved mainly in the PFC with the formation of the dispersion, preferably monodisperse, suspensions.

Such particles can be produced in a number of ways, including air drying, spray drying or drying by lyophilization, and should not be very small and may represent a heterogeneous mixture of particle sizes, ranging between 0.1 microns and 100 microns in diameter. In some cases it may be appropriate particles even Milli is erooga size.

The use of such stable suspensions are not limited parenteral introduction as indicated in the example above, or by oral administration, as described in Kirkland (1995). As PFC liquid solvent is non-toxic and non-reactive, it is an ideal solvent for delivery to the mucosa, including internal-lung delivery, nasal, ocular, rectal and vaginal delivery. A significant achievement of the present invention is the ability to produce a stable, sterile and non-irritating compositions for delivery to the mucosa even very unstable drugs or vaccines. In addition, the nature of PFC liquid is very dry and completely non-hygroscopic, which greatly assists in maintaining the sterility of these drugs for long term storage and occasional use, because microorganisms cannot grow in the absence of water.

Because volatile fluorosurfactants and chlorofluorocarbons have long been used as propellants in inhalers intended for drug delivery to the lungs, stable PFC compositions described in this text are ideal for small humanophobia STASIS of liquid droplets for internal-lung delivery. For such use is of a particle size which are intermittent suspended phase in the PFC droplets is of great importance and should not exceed a size of from 1 to 5 μm, preferably from 0.1 to 1 microns in diameter. For delivery to other mucous surfaces, for example, nose or eyes, the particle size is less important and could be up to 100 microns or even a few mm in diameter.

The water content of the microparticles is preferably not more than 4%, preferably less than 2% and ideally less than 1%.

Description of the drawings

Figure 1

Alkaline phosphatase (Sigma Aldrich Llt.) was stable in glass based on mannitol, 33,3%, calcium lactate, 33,3%, and degraded gelatin, 33,3% (VUSO, Croda Colloids Ltd.), dried by spraying in the form of microspheres and kept at 55°either as dry powder or as a stable suspension in performanceline. Activity has remained approximately at the 100%level (103% for 20 days and 94% within 30 days). The loss of activity was greater in the dry powder, which was suspended in PFC (about 80% of the activity remained).

Figure 2

Commercial tetanus vaccine (#T courtesy of Evans Medeva plc) was obtained in powder form suitable density, using the added calcium phosphate in 20% solution of trehalose. It was dried by lyophilization by spraying in liquid nitrogen, using a nozzle with two of truama fluid medium, followed by lyophilization of the frozen powder consisting of microspheres, in the freeze-dryer firm Labconco with the initial temperature -40°during the whole time of the primary drying. Humoral immune response of six groups of 10 Guinea pigs were measured after 4, 8 and 12 weeks after the injection of the same dose of ASSIST stable tetanus vaccine, reconstituted in buffered physiological solution or in the form of anhydrous preparations in oil or PFC.

Immune responses to all of the dried preparations were lower than the control fresh vaccine (data not shown), indicating a significant loss of potency during spray drying. Antigenic properties toxoid, assessed by uptake ELISA, did not change during the drying process. Based on these data it was concluded that the implementation of protection adjuvant aluminium hydroxide drying will require more effort.

The immune response of animals to STASIS of the vaccine, the density of which was summarized using calcium phosphate (group 3), was basically the same as the response to the control vaccine, reconstituted in aqueous buffer (group 1), and to a vaccine powder in oil (group 2), while the immune response of control animals, injectable non-aqueous solvents only (group 4 & 5), was not shown.

Des is th following examples are presented to describe the invention.


Dried spray particles in the PFC.

Particles were obtained by spray drying from aqueous solution using a spray dryer firm Labplant SD models 1, using sugar and other fillers. Conventional compositions were as follows:

A. Mannitol15% wt./about.
The calcium lactate in water15% wt./about.
Century trehalose15% wt./about.
Calcium phosphate in the water15% wt./about.

Particles were obtained using a nozzle with two jets of fluid with a hole of 0.5 mm in inner diameter. It was found that the optimum flow of air from the nozzle was half maximum flow, and the temperature in the drying chamber was 135°With inlet and 70-75°With output. Particles were collected in a glass cyclone and subjected to secondary drying in a vacuum furnace, through the drop in the temperature up to 80°With, for more than 4 hours. After cooling them suspended in the PFC using sonication. It is shown that for the processing of approximately 75% of the powder was enough to make a 30-second allocation of ultrasonic energy from titanium probe in the ultrasound Department of MSE MK 2, or place the powder up to 10 minutes in an ultrasonic BA is Yu Decon FS200 Frequency sweep.

Formed suspension was monodisperse and consisted of spherical glassy particles, ranging in size from about 0.5 to 30 microns with an average size of approximately 10 microns, as measured using a microscope. Particles based on mannitol/calcium lactate, went up layer consisting of PFC, in a few minutes, but easily was again exposed to suspendirovanie with a weak shaking. Particles, based on the trehalose/calcium phosphate, were selected for density by PFC and formed a stable suspension.

Dried spray powder particles of sugar glass suspended in performacne, performanceline and performanance at a concentration of 1, 10, 20 and 40% wt./about. It was found that they form a monodisperse suspension with a slight tendency towards aggregation. The addition of 0.1% perftordekalina acid to PFC led to the suppression slight tendency to aggregate on the surfaces. It was found that the suspension is easily passed through a 25 g needle by aspiration or release.


The stability of the suspension of the enzyme stabilized with glass in PFC

Alkaline phosphatase (Sigma Aldrich Ltd.) dried by spraying in machine company Labplant, as described above. The composition contained 33,3% wt./wt. mannitol, a 33.3% wt./wt. calcium phosphate and 33.3% wt./wt. degr the encrypted gelatin (VUSO, Croda colloids Ltd.). The dried enzyme was stored at a temperature of 55°in the form of a dry powder or in suspension in performanceline. The enzyme included in such microspheres consisting of sugar glass, based on mannitol, suspended in performanceline retained enzymatic activity, close to 100%, for more than 30 days at 55°With (Figure 1).


The efficiency of in vivo

Preclinical tests such compositions containing clinical tetanus vaccine (courtesy of Medeva plc), were undertaken jointly with the National Institute for biological standards and control (Metrology laboratory with the right of inspection and certification of measuring instruments of the world health organization). The results of this test showed that stable STASIS of the drug was fully equivalent water-based liquid vaccine in terms of its ability to immunize Guinea pigs for the development of a protective immune response (figure 2). The data obtained confirm that the suspension in the PFC is a ready-injection composition with the same bioavailability in vivo, as usual water-based liquid composition.


Particles obtained by freeze drying spray

Particles were obtained by spraying liquid droplets in the liquid and the OTE and then vacuum drying the frozen powder. The obtained particles were less dense than the spray dried powders, and formed a paste in PFC at concentrations higher than 20% wt./about. At lower concentrations they form a monodisperse suspension after ultrasonic treatment.

Conventional compositions used were as follows:

SubstanceThe final concentration wt./wt.
A. Trehalose100%
Century Trehalose50%
Calcium phosphate49,5%
Aluminium hydroxide0,5%


Crushed hydrophobic particles

Hydrophobic derivatives of sugar octaacetate sucrose and octaacetate trehalose easily reached glassy state or by a sudden cooling of the melt or during rapid drying from a solution of chloroform or dichloromethane. Their use was described as a matrix controlled release delivery of a drug (Roser et al "Solid delivery systems for controlled release of molecules incorporated therein and methods of making same", international publication PCT Pub No WO 96/03978, 1994).

Powder octaacetate trehalose was obtained by melting in a muffle furnace and rapid cooling of the melt on the stainless steel plate. The obtained glass dis and were crushed in a mortar with pestle and then in high-speed homogenizer to obtain a fine powder. Powder suspended in performacne, performanceline and performanance at a concentration of 1 and 10% wt./about. It was shown that they form a well dispersed suspension. It was found that such suspension easily pass through a 23 g needle.


Reconstitution in aqueous media

Based on the nature of the soluble particles of sugar glass and properties of PFC, it was hypothesized that the active substance in such suspensions must quickly be released in the body. In order to achieve complete release of the active substance particles were obtained, containing:

Trehalose20% wt./about.
Calcium lactate20% wt./about.
Lysinea 0.5% wt./about.
The dye Mordant Blue 91% wt./about.

The composition was dried by atomization, as described above, and added to performanance and performanceline with 20% wt./about dark blue, opaque suspensions. It was found that adding water to equal the amount of suspensions and shaking all the blue dye was actually released in the aqueous phase, which is formed of a transparent blue layer located on the surface of almost colorless PFC with clean, clear boundary between them.


From OUTSTA reactivity between particles in suspension

Because individual microspheres in PFC suspension is physically isolated from all other particles, potentially reactive substances can be together in the same suspension of individual particles without any risk of their interaction. When the sugar glass is dissolved, and molecules come together, interact.

In order to demonstrate this, there was obtained a suspension containing two types of particles, one (a) with the enzyme alkaline phosphatase and the other (b) with a colorless substrate, paranitrophenylphosphate.

The composition had the following composition:

a) Trehalose10% wt./about.
The sodium sulfate10% wt./about.
Alkaline phosphatase20 units/ml
In 5 mm Tris/HCl buffer, pH to 7.6
b) Trehalose10% wt./about.
The sodium sulfate10% wt./about.
Paranitrophenylphosphate0,44% wt./about.

In 100 mm glycine buffer, pH 10.2, containing 1 mm each of Zn++and Mg++chloride.

It was found that the suspension of powders in performanceline containing 10% wt./about. powder "a" and 10% wt./about. powder "b", does not develop any color reaction, but it remains white is for 3 weeks at 37° C.

Adding water and shaking the powder was dissolved in the lower aqueous phase. The enzymatic reaction proceeded for several minutes, producing an intense yellow coloration due to the formation of p-NITROPHENOL as-prepared sample, and this sample, which is maintained at a temperature of 37°C for 3 weeks.


The release of the product in the model of the "fabric of space"

In order to illustrate the possible behavior of the PFC suspensions when injected in vivo, was prepared with the model data of hydrated tissue space by obtaining 0,2% agarose gels in polystyrene flasks. Agarose gel was made of 0.1 ml of perftordekalina suspension from example 5 through a 25g needle. The result is a flattened white ball suspension. Over the following 5-10 minute white paint has passed from the lower part of the ball up, leaving a transparent ball PFC behind. As the enzyme and the substrate is released from the silica glass particles, they interact among themselves, thus formed reaction product yellow p-NITROPHENOL, which was then diffundiruet through the agarose in the next 1 hour.


Bring the density up to the appropriate level

Particles of sugar glass (i.e. trehalose), obtained by any out of the ordinary methods of drying, had typical values density of about 1.5 g/cm3. Tested perfluorocarbons usually had a density ranging from 1,68 to 2.03 g/cm3(table 1). For this reason, upon receipt of a suspension of particles of sugar glass tend to stay on the surface of the PFC layer, which leads to a drug, in which the active substance is unevenly distributed. However, the powders can be modified to obtain a stable suspension in the PFC, in which they have neutral buoyancy and do not settle and do not float on the surface. Such results can be achieved by adding high-density materials to the stage of particle formation. Such materials may be soluble or insoluble in water.

Water-insoluble materials

Tricalcium phosphate has a density of 3.14 g/cm3adopted as adjuvant for vaccines and practically insoluble in water. Powders containing about 50% calcium phosphate, have an increased density of about 2 g/cm3and 20% of solid particles form a stable suspension in performanance.

Examples of powders which, when content of 20% solids in PFC form a stable suspension include:

1 performanceline

SubstanceThe final concentration wt./wt.
A. the Requirement the shad 50%
Calcium phosphate50%
Century Trehalose47,5%
Calcium lactate10,0%
Calcium phosphate42,5%

2 performanance

SubstanceThe final concentration wt./wt.
Calcium lactate18,2%
Calcium phosphate45,4%

Other water-insoluble materials, which increased the density consisted of barium sulfate and titanium dioxide. Any non-toxic and insoluble material with the appropriate density could be used.

Water-soluble materials

Soluble salts such as sodium sulfate with a density of 2.7 g/cm3can also be used as increasing the density of agents. Following a stable suspension of the powder in performanceline:

SubstanceThe final concentration wt./wt.
The sodium sulfate50%

Other non-toxic water-soluble materials with the high density can also be used. It has been found that such compositions can cause discomfort after subcutaneous injection of Guinea pigs, possibly due to rapid dissolution of ionic salts at high concentrations.


The influence of selected density on the active substance in suspensions

Certain vaccines get adsorbed on the insoluble gels or particles, which serve as adjuvants. For these purposes, is widely used aluminum hydroxide and calcium phosphate. Such insoluble adjuvants may themselves be used to increase the density of the particles, which should be suspended. In this case, the material with high density is not completely inert, but actually adsorb the active macromolecule from the solution. It was necessary to show that such adsorption is not denaturised active substance. In order to check this, used alkaline phosphatase as a model of the active substance/vaccines.

Was prepared following solution

Adjuvant type
calcium phosphate10% wt./about. (Superphos Kemi a/s)
Trehalose10% wt./about.
ZnCl21 mm
Alkaline phosphatase20 units/ml

In 5 mm Tris-HCl, pH 7,6

Then the solution was thoroughly stirred for 10 minutes at 37°to carry out the adsorption of alkaline phosphatase using calcium phosphate. The change of absorbance per minute was determined, through the stage of centrifugation calcium phosphate, sampling supernatant and enzymatic kinetics, using as substrate p-nitrophenylphosphate and absorption measurement at a wavelength of 405 nm. The solution was spray dried to obtain a fine powder. In the supernatant was measured any desorption of the enzyme after re-hydration powder. The powder was suspended at a concentration of 20% wt./about. in performanance and found that it forms a stable suspension.

The test sampledabsorption/min (405 nm)
The original solution (25 μl)0,409
The supernatant from the solution above (25 ál)0,034
Re-hydrated powder
(25 ál of 20% wt./about. in water)0,425
The supernatant from the solution above (25 ál)0,004
20% wt./about. powder
performanceline (25 ál)0,430

In the experiment shown is: the density of particles can be adjusted according to the density PFC solvent by incorporating adjuvant calcium phosphate. In the process of obtaining particles significant desorption or loss of enzymatic activity was observed.

1. Composition for delivery of a stable, biologically active compounds to a subject, comprising particles of glass containing the specified biologically active compound, characterized in that the particles have a diameter in the range of 0.1 to 100 microns and suspended in the liquid, which includes at least one biocompatible perfluorocarbons, in which these particles do not dissolve.

2. The composition according to claim 1, characterized in that the particles obtained by spray drying.

3. The composition according to claim 1 or 2, characterized in that the particles comprise a mixture containing sugar and phosphate metal.

4. Composition according to any one of the preceding paragraphs in which the specified glass includes sugar glass, metacarbonate glass and/or phosphate glass.

5. Composition according to any one of the preceding paragraphs, characterized in that the particles contain a substance that promotes stekloobrazovanie.

6. Composition according to any one of the preceding paragraphs, characterized in that the liquid comprises a surfactant.

7. Composition according to any one of the preceding paragraphs, characterized in that the particles include sugar glass, formed from a sugar selected from the group consisting of trehalose, sucrose, raffinose, with ahiazu, glucopyranoside, glucopyranosyloxy, palatinite, lactate, monosaccharide alcohol or sugar molecules modified with hydrophobic side chains selected from the group consisting of octaacetate sucrose or octaacetate trehalose.

8. Composition according to any one of the preceding paragraphs, characterized in that the particles include phosphates of divalent metals or carboxylates of metals.

9. The composition according to claim 5 or any other item, dependent from it, characterized in that the specified connection, promoting stekloobrazovanie, selected from the group consisting of peptide, protein, dextran, polyvinylpyrrolidone, borate ion, calcium lactate, sodium polyphosphate and silicate or acetate (salt).

10. Composition according to any one of the preceding paragraphs, characterized in that the particle density corresponds to the density of the liquid.

11. Composition according to any one of the preceding paragraphs, characterized in that it includes a filler which passes these particles weak residual electrostatic charge so that the particles repel each other.

12. The composition according to claim 11, where the specified filler is an amino acid.


Same patents:

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SUBSTANCE: invention relates to arypyprazole anhydrous crystals B showing characteristic peaks in powdered roentgen rays diffraction at 2θ = 11.0°, 16.6°, 19.3°, 20.3° and 22.1°, specific infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1 in IR-spectrum, endothermic peak at 141.5° in thermogravimetric/differential thermic analysis and endothermic peak at 140.7° C in differential scanning calorimetry, arypyprazole A hydrate, to methods for their preparing, pharmaceutical compositions comprising arypyprazole crystals B and methods for their preparing. Invention provides reduced hygroscopicity of arypyprazole crystals B.

EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a biologically active microparticles composition comprising microparticles that involve: (a) polymer taken among group consisting of poly-(α-hydroxyacid), polyhydroxybutyric acid, polycaprolactam, poly-ortho-ester, polyanhydride and polycyanoacrylate, and (b) the first part of detergent that is bound with polymer, and also complex adsorbed on microparticles complex that comprises: (a) biologically active macromolecule, and (b) the second part of detergent wherein the first part of detergent and the second part of detergent comprise the same detergent or different detergents and wherein biologically active macromolecule is taken above group consisting of polypeptide, polynucleotide, polynucleoside, antigen, pharmaceutical agent, hormone, enzyme, transcription or translation mediating agent, metabolite, an immunomodulating agent and adjuvant. Also, invention relates to methods for preparing the composition and its applying. Invention provides improvement of adsorption of biologically active agents on microparticles surface in delivery systems, especially, for medicinal agents that are characterized with high sensitivity and complexity in their preparing based on the composition proposed.

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44 cl, 1 tbl, 1 dwg, 7 ex

FIELD: medicine, pharmaceutical technology, pharmacy.

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EFFECT: improved and valuable properties of composition.

16 cl, 2 ex

FIELD: medicine, antibiotics.

SUBSTANCE: invention relates to cephalosporin antibiotic - cefuroximaxetil that is used in treatment of bacterial infections. Invention proposes a new form of cefuroximaxetil not forming gel in contact with an aqueous solution. New form represents a solid solution of cefuroximaxetil in polymer and/or solid dispersion on adsorbent. New form of cefuroximaxetil can be used for preparing a granulate that can be used in oral pharmaceutical compositions as tablets or powder. Exclusion of gel-formation allows improving solubility of cefuroximaxetil that results to enhancing absorption of cefuroximaxetil in digestive tract.

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23 cl, 3 dwg, 8 tbl, 19 ex

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34 cl, 10 ex

FIELD: medicine, ophthalmology, pharmacology, pharmacy.

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4 ex

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4 cl, 4 tbl, 1 dwg, 4 ex

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EFFECT: higher efficiency of application.

23 cl, 15 ex, 19 tbl

FIELD: medicine.

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EFFECT: higher efficiency.

14 cl, 4 dwg, 7 ex, 5 tbl

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EFFECT: improved pharmaceutical properties of combinations.

23 cl, 3 dwg, 8 tbl, 19 ex

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EFFECT: improved and valuable properties of composition.

15 cl, 4 dwg, 4 tbl, 3 ex

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EFFECT: improved method for preparing, improved and valuable medicinal and pharmaceutical properties of preparation.

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