High pressure final sterilisation of pharmaceutic preparations and medical products

FIELD: medicine.

SUBSTANCE: invention belongs to sterilisation of pharmaceutic preparations in form of small particles or droplets dispersion and can be used in pharmaceutic industry. Sterilisation method of dynamic dispersion system which may have stable and unstable state includes impact of pressure higher than 0.25 MPa on small particles or droplets system for heating system to temperature higher than 100 °C during enough time for system's sterilisation, and system's decompression before it passes in unstable state. Invention refers to systems of dispersed micro- and nanoparticles in form of small particles or droplets which may have stable and unstable state. Particles or droplets of dispersion system include pharmaceutically active compound connected to excipient including superficially active compound.

EFFECT: invention provides stabilising of pharmaceutically active compound and excipient associates in form of dispersion system of particles or droplets in process of sterilisation at higher temperatures.

37 cl, 25 dwg, 1 tbl, 1 ex

 

The prior art INVENTIONS

The technical field

In accordance with the present invention it is proposed a method of sterilization of pharmaceuticals, for example, dispersions of small particles or drops of pharmaceutically active compounds using technologies final sterilization under high pressure and products from this connection.

The level of technology

The amount of organic compounds in prescription forms prepared for therapeutic or diagnostic effects that are poorly soluble or insoluble in aqueous solutions, is constantly increasing. These medicines are problems for their administration by routes of administration commonly used by medical personnel. One possible solution to this problem is to obtain small particles of insoluble potential drugs by making them dispersions of micro - and nanoparticles. Benefits derived from this formulation, may include higher stress, lower toxicity, greater limit of solubility and/or dissolution of the medicinal product, increased efficiency and enhanced stability of the medicinal product.

Thus, drugs that previously were not prepared for what I formulation in the system water-based, you can do suitable for administration in different ways. Preparations of dispersions of small particles of water-insoluble drugs can be administered by intravenous, oral, pulmonary, local, intrathecal, ophthalmic, nazalnam, buccal, rectal, vaginal, and transdermal routes. The optimal size range for these dispersions generally depends on the particular path, the characteristics of the particles, and other factors, for example, intravenously, it is desirable that the particle size was less than about 7 microns. The particles should be in this range of sizes and non-aggregated for safe passage through the capillaries without causing embolism (Alien et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978; Yokel et al., 1981).

Depending on the route of administration and other factors data dispersion of fine particles must satisfy certain standards of sterility. One of the useful methods of sterilization is a common final autoclaving dispersions of small particles at 121°C. it is Well known that pharmaceutical suspensions protect against the growth of the particles and/or aggregation during storage at normal temperatures by the presence of surface-active substances (surfactants) in recipes. However, even in the presence of data stabilizing surface-active substances and suspensions of small particles often at some with apani heat-sensitive and cannot withstand the final autoclaving. Pharmaceutically active ingredient, a surfactant and units drug/surfactant must remain physically and chemically stable during the entire sterilization cycle at 121°C. As is known, the chemical sensitivity of dispersions of fine particles to the final autoclaving is a function of both time sterilization and temperature. Ways to reduce chemical instability typically involve methods of high-temperature short-time sterilization. In this case, the conservation of thermolabile drugs and destruction of microorganisms based on the difference of velocities, respectively, chemical degradation and inactivation. A significant problem of this process is to ensure a sufficiently rapid heat transfer to uniform the temperature was in the whole volume of the product during a very short period of time.

It is very difficult to ensure physical stability of the aggregates of the drug/surfactant. Small particles are often aggregated, grow and/or decompose under the action of heat, making the final dispersion becomes unusable. In addition, aggregates of surfactants can be permanently separated from pharmaceutically Akti the aqueous compounds. For example, one mechanism of aggregation or coalescence of dispersions of solid submicron particles can be directly associated with the deposition of a stabilizing surfactant in the sterilization process at temperatures above the cloud point surfactants. The term "point cloud" refers to the separation of an isotropic solution of surface-active substances in a single phase with a high content of surfactants and one phase with a low content of surface-active substances. At these temperatures, the surfactant is often separated from the particles, causing aggregation and/or growth of unprotected particles. Therefore, the number of patents (for example, in U.S. patent No. 5298262, 5346702, 5470583 and 5336507) proposed the use of ionic and non-ionic modifiers cloud point to stabilize the suspension of particles during autoclaving. These modifiers increase point cloud point surfactants above 121°C, which prevents separation of the surfactant from the particles medicines and stabilize the particle growth during the final sterilization.

In U.S. patent No. 6267989 it is also shown that the most important for minimizing the growth and instability in the autoclave is optimal is a range of sizes. In patent No. 6267989 reported that the maximum stability occurs when at least 50% of the particles of the medicinal product, stabilized by surface-active substance, have srednevekovoi the particle size of 150-350 nm.

Hence, there remains a need to develop new and improved methods final sterilization of dispersions of fine particles in the pharmaceutical field, and the present invention is directed to this need.

Systems and solutions different from dispersions of particles, often require sterilization before use. Examples include dissolved pharmaceutical solutions, solutions for renal applications (e.g., peritoneal dialysis) and other forms of pharmaceutical drugs such as lipid emulsions. Other examples include medical devices, disposable, for example, packets with pharmaceutical drugs (often made of plasticized PVC or other plastics), packets with a blood dialysis apparatus, system for use in automated devices (e.g., devices, separation of blood, infusion pumps etc). These systems can be sensitive to traditional methods of sterilization, such as gamma radiation, ETO sterilization (ethylene oxide) or autoclaved. Nab is emer, containing glucose solutions degrade glucose or aggregation in the sterilization by conventional technologies. Therefore, there is also a need to create advanced sterilization technologies that ensure proper sterilization with small, or even zero, the risk for sterilisable system.

The INVENTION

In accordance with the present invention it is proposed a method of sterilization systems. These systems can be represented as, but without limitation the following composition, for example a dispersion of particles, and devices, such as containers, which may contain aqueous solutions, for example, pharmaceuticals. The method has the advantage of providing sterilization without significant reduction in effectiveness of these systems. The invention additionally provides sterilized pharmaceutical products. Suitable containers include any container which is stable under the conditions of the present method, including devices drug delivery containing medical solutions.

The method includes the supply of thermal energy to the system and maintaining the system under pressure of 0.25 MPa for a sufficient period of time to make it sterile. In a preferred embodiment, the system will be on stigate temperatures above 70°C. The stages of the energy supply and pressure simultaneously perform during the period of time at least sufficient to sterilize the system. Then the system can provide the ability to return to the temperature and pressure of the environment for use.

The method can be applied to empty containers or containers containing any of a wide variety of solutions, including solutions for parenteral administration, solutions for acute and chronic hemodialysis, hemofiltration or hemodiafiltration solutions for acute or chronic peritoneal dialysis, ambulatory peritoneal dialysis and automated peritoneal dialysis.

The method is especially useful for sterilization of solutions that contain glucose. The low temperature used for sterilization, minimizes the decomposition of glucose, which occurs at higher temperatures. Thus, the method can be used for sterilization of solutions containing glucose to glucose remained essentially without decomposition. In a preferred embodiment, more than about 75% glucose does not decompose, in the preferred embodiment, does not degrade more than approximately 80% of glucose, even more preferred are sterilized solutions, which does not degrade more than approx the positive 85% or about 90% or even more preferably more than about 95% of glucose.

These and other aspects and features of the present invention are discussed with reference to the accompanying drawings and description.

BRIEF DESCRIPTION of FIGURES

Figure 1 - the micelle;

figure 2 - reverse micelle;

figure 3 - lamellar phase;

4 is a hexagonal phase;

5 is a cubic phase;

6 is a graph of pressure and temperature from time to time;

7 - distribution curve of the particle size (example 1);

Fig - distribution curve of the particle size control sample (example 1);

Fig.9 - sterilization cycle high pressure (example 1);

figure 10 - distribution curve of particle sizes;

11 is a container for flowable materials;

Fig - multi-chamber container with a breakable insulating layer;

Fig mono - layer film;

Fig double - layer film;

Fig three - layer film;

Fig three - layer film;

Fig - four-layer film;

Fig - four-layer film;

Fig five - layer film;

Fig - six-plane film;

Fig - six-plane film;

Fig - layered film;

Fig - syringe;

Fig cartridge device for injection of a medicinal product; and

Fig device to enter the liquid.

DETAILED description of the INVENTION

Although the implementation of the present invention enabled the but in many different variants, in the drawings shown below are described in detail specific embodiments of the present invention on the assumption that the present description should be considered as an illustration of the principles of the invention and should not be considered as intended to limit the invention presents specific options for implementation.

In accordance with the present invention it is proposed a method of sterilization of the system without significantly reducing the suitability, stability and/or efficacy of the drug. According to the invention proposes a method of sterilization of a dynamical system (i.e. a system that is able to transition from stable state to unstable state), when this system is exposed to high pressure for a period of time sufficient to sterilize the system without causing a transition of the system from a stable state to an unstable state.

For the purposes of the present description, the term "sterilization" and its variants mean the destruction of bacteria, viruses, protozoa single-celled organisms or other biological organisms or fight with them in the system so that the system provided for a reduction in the risk of infection when using mammal, preferably a human. Preferred methods of the present invention should sterilize the system until everything is almost all biological organisms killed or made incapable of reproduction.

In a preferred embodiment, the method is used for the sterilization of pharmaceutical systems. The pharmaceutical preparation can be prepared using a number of technologies known in the art, and those that will be developed. Generally, the method provides a sterilisation system under high pressure. The method is suitable for sterilization under high pressure dispersion of small particles. According to the invention is additionally provided with sterilized pharmaceutical dispersion.

Sterilization under high pressure according to the present invention provide sterilization dispersions of small particles without an accompanying substantial collapse of pharmaceutically active compounds, decomposition of surface-active substances or changes in the accumulation of the drug/surfactant. In addition, heat is transmitted instantaneously throughout the dispersion due to rapid adiabatic heating of the drug at the stage of compression. It is assumed that sterilization under high pressure suitable for application to many dispersions of fine particles containing different pharmaceutical compounds in containers of a number of configurations.

In General, the method provides the sterilisation of pharmaceutical is Reparata under high pressure. The pharmaceutical preparation can be prepared using a number of technologies known in the art, and those that will be developed. Sterilization under high pressure are well suited for the sterilization of drugs in many different forms, including pharmaceutically effective compound in dry or powder form, liquid form, gaseous form, or dispersed to small particles or droplets in aqueous or organic media. In a preferred embodiment, subject to sterilization system will contain some amount of water. As proven, the presence of water provides especially effective reduction in the concentration of active microorganisms. It is widely known that for a message pharmaceutically active compounds resistance to aggregation and resizing using surface-active substances. Surfactants can be associated with a pharmaceutically active compound in any of many ways, is widely known in this field. Sterilization under high pressure in accordance with the present invention provide sterilization without causing the collapse of pharmaceutically active compounds or without causing significant removal of surfactants from pharmaceutically active compounds. With the people and products of the present invention do not require the use of chemical modifiers cloud point. The term "point cloud" refers to the increased turbidity of a pharmaceutical product, when changing the physical characteristics of the drug, for example, a change in temperature or pH, or other physical characteristics of forces surfactant be chipped off from the pharmaceutically active compounds.

It is assumed that sterilization under high pressure suitable for use with many organic compounds.

I. Pharmaceutically active compounds

The method according to the present invention is suitable for sterilization of pharmaceutical products in General. In preferred methods of the present invention pharmaceutically active ingredient be such that it is associated with dispersed hydrophobic region (for example, a hydrophobic phase of the aggregated surfactant, cyclodextrins cavity, oil droplets) in aqueous solution. Pharmaceutically active compounds may be selected from therapeutic agents, for the treatment of kidney, diagnostics, cosmetics, food additives and pesticides.

Pharmaceutically active means can be selected from many known classes, for example, but without limitation, the following: analgesics, anesthetics, analeptics, adrenergic tools, Adra is blokiruyuschij means, adrainolitiki, adrenocorticoid, agonists, anticholinergic agents, anticholinesterase agents, anticonvulsants, alkylating tools, alkaloids, allosteric inhibitors, anabolic steroids, drugs to reduce appetite, antacids, Antidiarrheals, antidotes, antifobicheskoe tools, antipyretics, Antirheumatic agents, psychotherapeutic tools, nervnobolnoj tools, anti-inflammatory agents, sedative, antiarrhythmic agent, antibiotics, anticoagulants, antidepressants, antidiabetics, ANTIEPILEPTICS, antifungal agents, antihistamines, antihypertensive agents, muscarinic holinoblokatora, protivomaljarijnye tools, antimalarials, antiseptics, antineoplastic means, Antiprotozoal drugs, immunosuppressants, Immunostimulants, antithyroid tools, antiviral agents, anxiolytic sedatives, astringents, beta-adrenergic blocking agents, contrast media, corticosteroids, cough tools, diagnostic tools, diagnostic imaging tools, diuretics, dopaminergic tools, hemostatic means, hematologist of the economic means, modifiers of hemoglobin, hormones, sleep AIDS, immunological tools, antihyperlipidemic or other means of regulation of lipid metabolism, muscarinic cholinergic receptors, muscle relaxants, parasympathomimetics tools, parathyroid calcitonin, prostaglandins, radiopharmaceutical tools, sedatives, sex hormones, anti-allergic medicines, irritants, sympathomimetic tools, thyroid tools, vasodilator, vaccines, vitamins and xantina. Antineoplastic or anticancer means, including, but without limitation, the following, paclitaxel and derivatives compounds and other antineoplastic means selected from the group consisting of alkaloids, antimetabolites, enzyme inhibitors, alkylating funds and antibiotics. A therapeutic agent may also be a biological product, which includes, but without limitation, the following, proteins, polypeptides, carbohydrates, polynucleotides and nucleic acids. Protein can be an antibody, which may be polyclonal or monoclonal.

Diagnostic tools include tools for radiographic studies and contrast media. Examples of means for x-ray examinations include WIN-8883 (ethyl-3,5-diacetamido-2,4,6-triiodothyronine is Insaat), also known as complex ethyl ether of diatrizoic acid (EEDA), WIN 67722, ie (6 ethoxy-6-oxohexyl-3,5-bis(acetamido)-2,4,6-triiodobenzoate; ethyl-2-(3,5-bis(acetamido)-2,4,6-triiodobenzoate)butyrate (WIN 16318); ethyldiethanolamine (WIN 12901); ethyl-2-(3,5-bis(acetamido)-2,4,6-triiodobenzoate)propionate (WIN 16923); N-ethyl-2-(3,5-bis(acetamido)-2,4,6-treatmentrelated (WIN 65312); isopropyl-2-(3,5-bis(acetamido)-2,4,6-triiodobenzoate)ndimethylacetamide (WIN 12855); diethyl-2-(3,5-bis(acetamido)-2,4,6-treatmentroxann (WIN 67721); ethyl-2-(3,5-bis(acetamido)-2,4,6-triiodobenzoate)phenylacetate (WIN 67585); [[3,5-bis(acetylamino)-2,4,5-triiodobenzoic]oxy]bis(1-methyl)ether of papandonatos acid (WIN 68165); and 3,5-bis(acetylamino)-2,4,6-triiodothyronine-4-(ethyl-3-ethoxy-2-butenoate)ester of benzoic acid (WIN 68209). Preferred contrast agents include those substances which, according to the calculations, relatively quickly decomposed under physiological conditions, which minimizes any inflammatory reaction caused by the particles. Decomposition can occur as a result of enzymatic hydrolysis, solubilization of carboxylic acids at physiological pH or other mechanisms. Therefore, the preferred may be slightly soluble iodinated carboxylic acids, such as iodipamide, diacrisia acid and matricola acid, together with hydrolytical and unstable ladirovannye products for example, WIN 67721, WIN 12901, WIN 68165 and WIN 68209 or other.

Other radiopaque substances include, but without limitation, the following preparations in the form of particles, means for imaging using nuclear magnetic resonance, for example, gadolinium chelates, or other paramagnetic contrast agents. Examples of these compounds are gadopentetate dimeglumine (Magnevist®) and gadoteridol (Prohance®).

A description of these classes of therapeutic agents and diagnostic tools and food lists each class can be found in the publication Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press, London, 1989, which is incorporated into this description by reference and is part of it. Therapeutic agents and diagnostic tools are commercially available and/or can be prepared by methods known in this field.

Means for treatment of kidney include solutions for continuous ambulatory dialysis, automated peritoneal dialysis and hemodialysis.

Cosmetic is any active ingredient capable of cosmetic effects. Examples of these active ingredients can be, inter alia, softeners, moisturizers, means slowing down the formation of free radicals, anti-inflammatory agents, vitamins, depigmentosus assets, PREV the th rash, protivoseborainey tools, keratolytic remedies, weight loss products, toners for the skin and sunscreen and, in particular, linoleic acid, retinol, retinoic acid, complex alkalemia esters of ascorbic acid, polyunsaturated fatty acids, esters of nicotinic acid, tocopherol nicotinate, unsaponifiable matter of rice, soybeans or Shea butter, ceramides, oxyacids, for example, glycolic acid, derivatives of selenium compounds, antioxidants, beta-carotene, gamma-oryzanol and sterilisers. Cosmetic products are commercially available and/or can be prepared by methods known in this field.

Examples of food additives proposed for use in practice of the present invention, include, but without limitation, the following, proteins, carbohydrates, water-soluble vitamins (such as vitamin C, B vitamins and the like), fat-soluble vitamins (such as vitamins A, D, E, K and the like) and plant extracts. Food additives are commercially available and/or can be prepared by methods known in this field.

It should be understood that the term pesticides includes herbicides, insecticides, acaricides, nematicides, remedies against ectoparasites and fungicides. Examples of classes of compounds that may have pesticides on the present the invention, include urea, triazine, triazole, carbamates, esters of phosphoric acid, dinitroanilines, morpholines, acylalanines, pyrethroids, esters benzyl acid, simple diphenyl ethers, and polycyclic golozhabernyi hydrocarbons. Specific examples of pesticides in each of these classes listed in the manual Pesticide Manual, 9th Edition, British Crop Protection Council. Pesticides are commercially available and/or can be prepared by methods known in this field.

In a preferred embodiment, pharmaceutically active compounds are poorly soluble in water. Under "weak solubility" refers to the solubility of compounds in water below about 10 mg/ml and, preferably, below 1 mg/ml. Data slightly soluble in water funds are most suitable for preparations in the form of aqueous suspensions, as ways to create recipes of these tools in water limited environments.

The present invention can practically be done with water-soluble pharmaceutically active compounds in some cases by incorporating these compounds in the solid hydrophobic dispergirovannoyj phase (e.g., polylactate-polyglycolide copolymer or solid lipid nanoparticles), or encapsulation of these compounds into the surrounding unit surface-act the main substances which is impenetrable for pharmaceutical compounds. Examples of aggregates of surfactants include, but without limitation, vesicles and micelles. Examples of water-soluble pharmaceutical agents include, but without limitation, the following, simple organic compounds, proteins, peptides, nucleotides, oligonucleotides, and carbohydrates.

II. The particle size of the dispersion and route of administration

When the pharmaceutical agents of the present invention are in the form of particles (i.e., not dissolved in the solvent), the particles will have an average effective particle size, typically less than approximately 100 μm, when measured by using the techniques of dynamic light scattering, for example, photocorrelation spectroscopy, diffraction of laser radiation small-angle laser scattering (LALLS), srednedushevogo of laser scattering (MALLS), shadow methods (for example, by the method of Kotler), rheology, or microscopy (light or electron). However, particles can be prepared with sizes in a wide range, for example, from about 100 μm to about 10 nm, from about 10 μm to about 10 nm, from about 2 microns to about 10 nm, from about 1 μm to about 10 nm, from about 400 nm to about 50 nm, from approx the flax 200 nm to about 50 nm, or any range or combination within the above ranges. The preferred average effective particle size depends on such factors as the intended route of administration, formulation, solubility, toxicity, and bioavailability of the compounds.

So that the particles were suitable for parenteral administration, the average effective particle size should preferably be less than about 7 microns, and preferably less than about 2 microns, or any range or combination within the above ranges. Parenteral administration includes intravenous, intraarterial, intrathecal, intraperitoneal, intraocular, intraarticular, an intradural, intraventricular, intrapericardially, intramuscular, intradermal or subcutaneous injection.

The particle sizes for dosage forms for oral administration may exceed 2 μm. The particle sizes can range up to approximately 100 μm, provided that the particles have sufficient bioavailability and other characteristics of dosage forms for oral administration. Dosage forms for oral administration include tablets, capsules, pills in the form of capsules, capsules, soft and thick gel or other medium for the introduction of medicines oral route.

In addition, the present invention is applicable to particles in pharmaceutical preparations is automatic active compounds in the form, suitable for pulmonary administration. The particle sizes for dosage forms for pulmonary applications can exceed 500 nm, and typically less than about 10 microns. Particles in suspension can be aerotolerant and enter via atomizer for pulmonary administration. Alternatively, particles can be introduced in the form of a dry powder using the inhaler for dry powder after removal of the liquid phase of the suspension or dry powder can be resuspendable in non-aqueous propellant for the introduction of the dosing inhaler. A suitable propellant, for example, HFC (HFC) type HFC-134a (1,1,1,2-Tetrafluoroethane) and HFC-227ea (1,1,1,2,3,3,3-Heptafluoropropane). Unlike chlorofluorocarbons (CFC) HFC or less not destroy the ozone layer.

Particles and droplets of organic compounds with dimensions in the above ranges collectively referred to as fine particles.

Dosage forms for administration by other routes, for example, nazalnam, local, eye, buccally, rectal, vaginal, transdermal and the like also can be prepared from particles made in accordance with the present invention.

In accordance with the present invention can be sterilized by other forms of solutions. Examples of these solutions include pharmaceutical preparations for parenteral administration and RA what works for renal dialysis, for example, solutions for hemodialysis and peritoneal dialysis.

III. The preparation of dispersions of fine particles

There are many technologies for the preparation of pharmaceutical preparations from small particles of pharmaceutically active compounds. Discussed below sterilization suitable for sterilization data of pharmaceuticals. The following is a brief description of typical, but not exhaustive examples of methodologies to create small particles of pharmaceutically active compounds.

A. Technologies for supplying energy for the formation of dispersions of fine particles

The method of preparation of dispersions of small particles using technologies such as energy supply typically includes a step consisting in that the pharmaceutically active compound, which sometimes should be called medicinal product, introducing a volume of a suitable medium such as water or water based mud containing at least one of the following surface-active substance, or other liquid, in which the pharmaceutical compound insignificant soluble to form presuspension. To presuspension bring energy for the formation of a dispersion of particles. The energy sum of the mechanical crushing, grinding in a Bead mill, grinding ball mill, grinding in a hammer mill, grinding in p is Inoi mill or wet grinding. These technologies are described in U.S. patent No. 5145684, which is included in the present description by reference and is part of it.

Technology energy supply additionally include the impact on presuspension much effort shift, including cavitation, shear or impact efforts, using microfluidizer. In accordance with the present invention further provides a supply of energy in presuspension using a piston homogenizer or counter-flow homogenizer of the type described in U.S. patent No. 5091188, which is included in the present description by reference and is part of it. Suitable piston homogenizers are sold under the name EMULSIFLEX firm Avestm and French Pressure Cells firm breakers Instruments. Manufacturer of suitable microfluidizer is firm Microfluidics Corp.

The phase of the energy supply can also be performed using technologies ultrasonic treatment. The phase of the ultrasonic treatment can be performed using any suitable device for ultrasonic treatment, for example, Branson Model S-450A or Cole-Panner 500/750 Watt Model. These devices are widely known in the industry. Typically, a device for ultrasonic treatment contains ultrasonic horn emitter or probe that is inserted into presuspension for radiation energy of the sound waves in the solution. Device to access ODI ultrasound in the preferred embodiment of the invention is used at a frequency from about 1 kHz to about 90 kHz and in a more preferred embodiment, from about 20 kHz to about 40 kHz or any range or combination within the above ranges. The dimensions of the probe may change and, preferably, have certain values, for example, 1/2 inch or 1/4 inch or something similar.

Regardless of the technology used for supplying energy dispersion of fine particles shall meet the applicable requirements to ensure sterility before use. Sterilization can be performed using the following technologies sterilization under high pressure.

B. Methods of deposition for the preparation of dispersions of submicron particles

Dispersion of fine particles can also be prepared by well-known deposition technologies. Below are the deposition technology used to obtain dispersions of submicron solid particles.

Methods microsurgery

One example of how microsurgery proposed in U.S. patent No. 5780062, which is included in the present description by reference and is part of it. In U.S. patent No. 5780062 describes the method of deposition of organic compounds, comprising the following steps: (I) dissolving the organic compound miscible in water first solvent; (II) prepare a solution of polymer and amphiphilic substances in the water the second solvent, with an organic compound, essentially, does not dissolve the IMO in this second solvent, resulting in the creation of the complex polymer/amphiphilic substance; and (III) mixing the solutions from steps (I) and (II) so as to cause the deposition of unit organic compounds and complex polymer/amphiphilic substance.

Another example of a suitable deposition method described in jointly considered and owned by a common owner applications for U.S. patent No. 09/874499, 09/874799, 09/874637 and 10/021692, which is incorporated into this description by reference and are a part of it. The described methods include the following steps: (1) dissolved organic compound miscible in water first organic solvent to create a first solution; (2) mixing the first solution with the second solvent or water to precipitate organic compounds to create presuspension; and (3) bring energy to presuspension in the form of mixing with a large shearing force or heat to ensure the dispersion of small particles. At least one undermentioned possible surface modifier may be introduced into the first organic solvent or the second aqueous solution.

Methods of emulsion precipitation

One suitable technology for the deposition of the emulsion described in jointly considered and owned by a common owner with the application for U.S. patent No. 09/964273, which is incorporated into this description by reference, and is the th part. In this approach, the method includes the following steps: (1) provide a multiphase system containing organic phase and aqueous phase, while the organic phase contains the pharmaceutically active compound; and (2) process the ultrasound system for evaporation of organic phase to cause precipitation of the compound in the aqueous phase to form a dispersion of small particles. The stage of the multiphase system contains the following stages: (1) mixing mixing with water, the solvent is pharmaceutically active compound for the formation of the organic solution, (2) prepare a solution of water-based with at least one surface-active compound and (3) mixing the organic solution with the aqueous solution for formation of a multiphase system. The step of mixing the organic phase and the aqueous phase may include the use of piston homogenizers, colloid mills, high speed mixing equipment, extrusion equipment, hand equipment to activate or shaking, microfluidizer or other equipment or technology to provide the regime with great effort shift. Raw emulsion will contain oil drops in water with dimensions of approximately less than 1 micron in diameter. Raw emulsion is treated with ultrasound is m to form a more finely dispersed emulsion and, ultimately, ensure the dispersion of small particles.

Another approach to the preparation of dispersion of fine particles described in jointly considered and owned by a common owner with the application for U.S. patent No. 10/183035, which is incorporated into this description by reference and is part of it. The method includes the following steps: (1) provide the raw dispersion of multiphase systems containing organic phase and aqueous phase, while the organic phase contains the pharmaceutically active compound; (2) provide energy to the raw dispersion for formation of a fine dispersion; (3) freeze fine dispersion and (4) lyophilizer fine dispersion to obtain fine particles of pharmaceutical compounds. Small particles can be sterilized using the following technologies, or small particles can be recovered in the aquatic environment and sterilized.

The stage of the multiphase system contains the following stages: (1) mixing mixing with water, the solvent is pharmaceutically active compound for the formation of the organic solution, (2) prepare a solution of water-based with at least one surface-active compound and (3) mixing the organic solution with the aqueous solution for formation of a multiphase system. The step of mixing the organic phase and aq is phase may include the use of piston homogenizers, colloid mills, high speed mixing equipment, extrusion equipment, hand equipment to activate or shaking, microfluidizer or other equipment or technology to provide the regime with great effort shift.

The deposition solvent-precipitant

Dispersion of fine particles can be prepared using technologies deposition solvent precipitator described in U.S. patent No. 5118528 and 5100591, which is incorporated into this description by reference and are a part of it. The method includes the following steps: (1) preparing a liquid phase of biologically active substances in a solvent or mixture of solvents, to which may be added, at least one surfactant; (2) preparing a second liquid phase of the precipitator or a mixture of precipitators, while the precipitator is able to mix with the solvent or mixture of solvents substances; (3) connect the solutions (1) and (2) under stirring and (4) to remove unwanted solvents for the formation of a dispersion of fine particles.

Deposition inversion phases

Dispersion of fine particles can be created using deposition with inverse phases, as proposed in U.S. patent No. 6235224, 6143211 and the application for U.S. patent No. 2001/0042932 that every traveler included in the present description by reference and are a part of it. the Ermin inversion of phases used to describe physical phenomena, through which the polymer is dissolved in the solvent system dispersing medium, is converted into a solid macromolecular network structure, in which the polymer is a continuous phase. One of the ways you can call the inversion phase is the addition of a precipitant in the dispersing medium. The polymer undergoes a transition from a phase in an unstable two-phase mixture of enriched polymer and depleted in polymer fractions. Micellar droplet precipitator in the enriched polymer fractions act as nucleation centers and become coated with the polymer. In U.S. patent No. 6235224 shown that the phase inversion of polymer solutions under some conditions may lead to spontaneous formation of discrete particles, including nanoparticles. U.S. patent No. 6235224 contains descriptions of dissolution or dispersion of the polymer in the solvent. Pharmaceutical tool is also dissolved or dispersed in the solvent. Polymer, the tool and the solvent form total mixture homogeneous phase, while the solvent is in a homogeneous phase. The mixture is then injected with at least a tenfold excess mixing precipitator to cause the spontaneous formation of microencapsulating microparticles funds with an average particle size of from 10 nm to 10 μm. The particle size depends on the volume relations of the RA the maker:precipitator, the concentration of the polymer solution viscosity of the polymer-solvent molecular weight of the polymer and characteristics of couples solvent-precipitant.

Precipitation change in pH

Dispersion of fine particles can be created using technologies such as deposition by changing pH. These technologies typically include the step consisting in the fact that dissolve the drug in a solution with a pH at which the drug is soluble, followed by a step consisting in the fact that changing the pH to a level at which the medicinal product is no longer soluble. The pH can be acidic or basic depending on the specific pharmaceutical compounds. Then the solution is neutralized to form a dispersion of small particles. One suitable method of precipitation with a pH change is proposed in U.S. patent No. 5665331, which is included in the present description by reference and is part of it. The method comprises the step consisting in that the dissolved pharmaceutical tool in conjunction with the modifier crystal growth (CGM) in alkaline solution and then neutralizing the acid solution in the presence of a suitable modifying the surface of the surface-active substance or substances to form a dispersion of fine particles of the pharmaceutical means. For phase deposition can follow the steps diafiltration and cleaning disperse is then bringing the concentration of the dispersion to the desired level.

Other examples of methods of deposition of change of pH is described in U.S. patent No. 5716642, 5662883, 5560932 and 4608278, which is incorporated into this description by reference and are a part of it.

The method of deposition of infusion

Suitable deposition technology infusion for the formation of dispersions of fine particles described in U.S. patent No. 4997454 and 4826689, which is incorporated into this description by reference and are a part of it. First, a suitable solid compound is dissolved in a suitable organic solvent for the formation of a solvent mixture. Then besieging precipitator, miscible organic solvent, pour in the solvent mixture at a temperature of from about -10°C to about 100°C and rate of infusion from about 0.01 ml / min to about 1000 ml per minute per volume of 50 ml to form a suspension of precipitated non-aggregated solid particles connections with essentially the same average diameter less than 10 microns. Suitable activation (e.g., mixing) pour the solution with a precipitating precipitator. The precipitator may contain a surfactant for messages particles resistance to aggregation. Then the particles sephirot from the solvent. Depending on solid compounds and the desired particle size parameters of temperature, the ratio of precipitant to the races is Writely, the rate of infusion, stirring speed and volume can be changed in accordance with the present invention. The size of the particles is proportional to the ratio of the volume of the precipitator:the solvent and the temperature of the infusion and inversely proportional to the rate of infusion and the stirring speed. Precipitating the precipitator may be aqueous or non-aqueous depending on the relative solubility of the compounds and the desired suspending medium.

The deposition temperature change

The technology of deposition temperature can also be used for the formation of dispersions of small particles. This technology is described in U.S. patent No. 5188837, which is included in the present description by reference and is part of it. In the embodiment of the invention lipoid spheres obtained using the following steps: (1) is melted or dissolved substance, for example, a drug that is subject to introduction into the molten carrier, to form liquid liquid fraction of the substance to be introduction; (2) impose a phospholipid with an aqueous medium in the molten substance or carrier at a temperature higher than the melting point of the substance or carrier; (3) mixing the suspension at a temperature above the melting temperature of the carrier until then, until you get a homogeneous fine product; and then (4) is rapidly cooled, the product p and the temperature, equal to or below room.

The deposition by evaporation of solvent

The technology of deposition by evaporation of the solvent is described in U.S. patent No. 4973465, which is included in the present description by reference and is part of it. U.S. patent No. 4973465 provides methods for preparation of microcrystals, which includes the following steps: (1) provide the solution of the pharmaceutical composition and phospholipid dissolved in a common organic solvent or combination of solvents, (2) the solvent is evaporated or solvents, and (3) suspended film obtained by evaporating the solvent or solvents in the aqueous solution with intensive stirring to form a dispersion of small particles. The solvent can be removed by the supply of energy to the solution to evaporate the amount of solvent sufficient to cause deposition of the connection. The solvent can also be removed using other well-known technologies, for example, by placing the solution in a vacuum or by blowing nitrogen through the solution.

Precipitation interaction

The deposition of the interaction contains the stages of dissolution of the pharmaceutical compound in a suitable solvent to form a solution. The connection should be entered in the quantity equal to or below the saturation limit of the compound in the solvent. The connection Modific the shape through interaction with the reagent or by modification in response to supply of energy, for example, heat or UV radiation or the like, so that the modified compound had poor solubility in a solvent and deposited from a solution by the formation of small particles.

The deposition of the compressed fluid medium

Appropriate technology for the deposition of the compressed fluid medium is described in the publication WO 97/14407 in the name of Johnston, which is incorporated into this description by reference and is part of it. The method comprises the steps consisting in the fact that dissolve water-insoluble drug in a solvent to form a solution. Then the solution is sprayed into the compressed fluid medium, which may be a gas, liquid or the fluid in supercritical state. The introduction of the compressed fluid in the solution of the solute in the solvent causes the dissolved substance to reach or come close to the saturated state and deposited in the form of fine particles. In this case, the compressed fluid acts as a precipitant, which reduces the energy density of bonding solvent, in which the dissolved drug.

Alternatively, the drug can be dissolved in the compressed fluid, which is then dispersed in the aqueous phase. The rapid expansion of the compressed fluid reduces the dissolving ability of the fluid in ceredi, forces the dissolved substance is deposited in the form of fine particles in the aqueous phase. In this case, the compressed fluid acts as a solvent.

For messages particles resistance to aggregation on the technology used, the surface modifier, for example, surface-active substance.

There are many other methodologies for the preparation of dispersions of small particles. In accordance with this invention proposes a methodology for the final sterilization of these dispersions without a significant impact on the effectiveness of the drug.

IV. Types of dispersions of fine particles

The dispersion of fine particles can be created from the hydrophobic region of the water system (e.g., aggregates of surfactants, cyclodextrins cavity drops of oil) and pharmaceutically active compounds or of the hydrophobic area if this area is pharmaceutically active. The hydrophobic region may be associated with a pharmaceutically active compound through a number of different mechanisms in the dispersion of small particles. For example, a hydrophobic region may be associated with a pharmaceutically active compound covalent bond and ionic bond, dipole-dipole interactions, induced dipole-dipole interactions or van der Waals forces. Additionally, the pharmaceutically active compound can be encapsulated in the hydrophobic region.

A. Hydrophobic region

Aggregates of surfactants

As you know, the hydrophobic region formed in aqueous solution from a single surfactant or combination of surfactants, amphiphilic type in aqueous solution (e.g., phospholipids). Aggregates of surfactants include micelles (figure 1), reverse micelles (figure 2), lamellar form mixed micelles, reverse mixed micelles (figure 3), the hexagonal phase inverse lamellar form (figure 4), the cubic phase reverse hexagonal phase (figure 5), the inverse cubic phase, a sponge phase L3, reverse sponge phase L3 and intermediate phases. The formation of normal or reverse phase depends on the type of surfactant, concentration of surfactant, temperature and pressure. Chelate should also be attributed to this class.

Figure 1 shows the micelle 10 with numerous amphiphilic molecules 12 that are located on a circle at a certain distance from each other and containing nonpolar hydrophobic tails 14 of amphiphilic molecules, continuing axially inward with the formation of the core 16, and a polar hydrophilic head 18 extending radially outward from the core with the formation of the surface 19.

Figure 2 shows the reverse micelle 2, which is similar to the micelle in figure 1 in all respects, except that the polar head 18 continue inside to the core and non-polar tails extend outward from the core. This will be true for the phases in General and their inverse versions. Therefore the figure for each feedback form is omitted.

Figure 3 shows the lamellar phase 30. Lamellar phase 30 contains spatially dispersed amphiphilic molecules 12, forming a multi-level two-layer structure 32. The space between the two structures 32 and the space between the hydrophobic tails known as columnar layers 34 and 36. Columnar layer 34 is hydrophobic, and columnar layer 36 is hydrophilic.

Figure 4 shows the hexagonal phase 40. The hexagonal phase can be represented as a sequence of normal micelles (figure 1), located one above the other with the formation of tubular structures 42.

Figure 5 shows one example of the cubic phase 50. So far identified seven cubic phases and structure tentatively described. Continuous in both sides of the cubic phase 50 contains a sequence of two-layer structures 32, which form a connected mesh of intersecting pipes providing water pores 52.

Phase L3 described in U.S. patent No. 5531925, which is included in the present description by reference and is a part of it. Phase L3 is very similar to the cubic phase, but lacks long-range order of the cubic phase.

The complexing agents

Hydrophobic zones can also be created in an aqueous solution by the introduction of complexing agents such as cyclodextrins. Cyclodextrins are also widely used to interact with insoluble drug compound in aqueous solution, as described in U.S. patent No. 4764604, which is included in the present description by reference and is part of it.

Two-phase dispersion

Hydrophobic region in the water system can also be made from multiple heterogeneous two-phase systems, including emulsions, microemulsions, suspensions, and other systems.

As mentioned previously, the present invention can actually be implemented with any of these drugs, in which the pharmaceutically active compound linked to a hydrophobic region for formation of a dispersion of fine particles, or of the hydrophobic region, if it is pharmaceutically active. Pharmaceutically active compound may be embedded in the hydrophobic region of any of the drugs mentioned types through many of the above mechanisms. Many of these systems are described in detail in the publication “Surfactants and Polymers in Aqueous Solution”, 2003, John Wiley and Sons, which is incorporated into this description by reference and t is aetsa part of it.

V. Surfactants

Especially important and safe classes of amphiphilic surfactants include phospholipids. Phospholipids are usually derivatives of triglyceride containing two hydroxyl groups of ester of glycerol, associated with fatty acids (forming polar tail), and one terminal hydroxyl group associated with the phosphoric acid. Phosphoric acid, in turn, is associated with another connection (e.g., choline, ethanolamine, ethylamine, glycerin or L-serine) with the formation of the polar head group. Suitable phospholipids include, for example, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination of both. The phospholipid may be saturated salt or desalted, gidrirovanny or partially gidrirovanny or natural, semi-synthetic or synthetic.

Suitable surfactants according to the present invention include anionic surfactants, cationic surfactants, nonionic surfactants, zwitterionic surfactants or surface biologically-active molecules. An appropriate the district and zwitterionic surfactants include, but without limitation the following, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkylpolyoxyethylene, sodium alginate, dioctylsulfosuccinate sodium, esters of glycerin, sodium carboxymethylcellulose, holaway acid and other bile acids (for example, holaway acid, deoxycholate acid, glycocholic acid, taurocholic acid, glycobiotechnology acid) and their salts (for example, deoxycholate sodium etc). Suitable cationic surfactants include, but without limitation, the following, Quaternary ammonium compounds such as benzalkonium chloride, bromide, cetyltrimethylammonium, chloride of lauryldimethylamine, hydrochloride of acylcarnitine or halides alkylpyridine.

Suitable nonionic surfactants include: polyoxyethylene ethers of fatty alcohols (Macrogol and Brij), polyoxyethylene esters of sorbitol and fatty acids (Polysorbate), polyoxyethylene esters of fatty acids (Myrj), esters of sorbitan (Span), glycerylmonostearate, glycols, polypropylenglycol, cetyl alcohol, cetosteatil alcohol, stearyl alcohol, spirits of alkylaryl polyethers, copolymers of the type polyoxyethylene-polyoxypropylene (poloxamer), poloxamine, methylcellulose, hydroxine lulose, hydroxypropylcellulose, hypromellose, noncrystalline cellulose, polysaccharides including starch and starch derivatives, for example, gidroksietilirovanny starch (HES), polyvinyl alcohol and polyvinylpyrrolidone. In one of the preferred embodiments of the invention, the nonionic surfactant is a copolymer of polyoxyethylene and polyoxypropylene and preferably a block copolymer of propylene glycol and ethylene glycol. These polymers are present in the market under the trade name POLOXAMER (POLOXAMER), sometimes also referred to as PLURONIC®and sold by several vendors, including BASF, Spectrum Chemical and Ruger. Some polyoxyethylene esters of fatty acids containing short alkyl chain. An example of such a surfactant is SOLUTOL®HS 15, polyethylene-660-hydroxystearate, produced by BASF Aktiengesellschaft.

Surface-active biological molecules include molecules like albumin, casein, heparin, hirudin or other relevant proteins.

In dosage forms for oral administration can be used, at least one of the following excipients: gelatin, casein, lecithin (phosphatides), Arabian gum, cholesterol, tragakant, stearic acid, benzalkonium chloride, calcium stearate is, glycerylmonostearate, cetosteatil alcohol, emulsifying wax for cetomacrogol, esters of sorbitol, polyoxyethylene simple alkalemia esters, for example, ethers type macrogol, for example, cetomacrogol 1000, polyoxyethylene derivatives of castor oil, polyoxyethylene esters of sorbitol and fatty acids, for example, commercially available tools Tweens™, glycols, polyethyleneamine, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose, noncrystalline cellulose, magnesium aluminosilicate, triethanolamine, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). Most of these fillers are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, publishing house of the Pharmaceutical Press, 1986. The surface modifiers are commercially available and/or can be prepared using techniques known in the field. At least two of the surface modifier can be used in combination.

VI. The stabilizing effect of high pressure on the dispersion of fine particles

High pressure can stabilize the system of small particles is the exploits of a number of different mechanisms, which can be either thermodynamic (volume of the reaction mixture)or kinetic (volume activation) origin. In addition, the high pressure may be chemically and/or physically stabilized pharmaceutically active ingredient, a surfactant and/or Assembly of a medicinal product/hydrophobic region during the entire sterilization cycle. An example of thermodynamic stabilization is the high pressure at the point of turbidity polyoxyethylene surfactants. It is known that the cloud point of these systems increase in compression due to the strengthening of the hydrogen bonds and the destruction of hydrophobic communication. Therefore, dispersion of small particles that are unstable during autoclaving due to deposition at the point of turbidity, can be stabilized by performing the final sterilization under such elevated pressures, at which point the cloud point surfactant system is superior to 121°C.

Example 1

Sterilization under high pressure nanosuspension Itraconazole

Prepared 1% nanosuspension of Itraconazole, containing 0.1% poloxamer 188, 0.1% dezoksiholatom and 2.2% glycerol, using the combined procedure microsurgery-homogenization (application for U.S. patent No. 2002/0127278 A1). The initial size distribution of erenee method static light scattering (Horiba LA-920), shown in Fig.7.

For the positive control first sterilized 5-ml sample of nanosuspension using the normal cycle of autoclaving at 121°C for 15 minutes. The result has been a substantial aggregation of particles, as seen from the light scattering data on Fig. The aggregation of this type is typical for nanosuspension, stabilized by surfactants, the point of turbidity less than 121°C (point cloud for Poloxamer 188 is approximately equal to 110°C).

In contrast, when a similar nanosuspension sterilized using a sterilization cycle, the high pressure, shown in Fig.9, the resulting size distribution of particles in 1% of nanosuspension of Itraconazole remained entirely unchanged, as shown in figure 10.

VII. Equipment and principles of sterilization under high pressure

Sterilization high-pressure devices usually contain the sterilization chamber to control temperature and pressure. The chamber contains a cover which tightly closed during use. The device is capable of providing high pressure up to 1000 MPa. The apparatus also includes a heat source that can heat sterilization chamber to 120°C and above.

The method of using the device includes the steps consisting in the fact that provide a system required in the Oh form. In the case of pharmaceuticals, the drug will be a powder form, in a solution or a water dispersion of particles, In a preferred variant of the invention, the pharmaceutical product contained in the container, which varies in size or shape depending on the pressure supplied to the container. These containers can include a flexible polymeric container or other flexible container, for example, the cylinder of the syringe, a cartridge for a needleless syringe or dosing pump. Below is a detailed description of the data containers. In accordance with the present invention assumes the introduction of pharmaceutical product directly in the sterilization chamber.

Pharmaceutical drug is placed in a sterilization chamber in which the product will be subjected to pressure change, temperature change, or both simultaneously. In contrast to existing autoclaves for sterilization of containers for droppers and the like, which provide a pressure just below 0.25 MPa, under this method, the drug is subjected to the action of pressure of more than 0.25 MPa. In a preferred embodiment of the invention, the drugs will be subjected to the action of pressures from 0.25 MPa to about 1500 MPa, more preferred embodiment, from 0.25 M to the a to about 700 MPa and in any range or combination of ranges within the specified limits.

In accordance with the present invention additionally includes the effects of temperature and pressure so as to reduce to a minimum the period during which the drug is exposed to a temperature above 25°C. Preferably the temperature of the system will exceed 70°C, preferably 90°C, even more preferably 100°C and in the most preferred embodiment of 120°C and above. Use a variety of graphs of temperature and pressure, depending on time, for example, a graph shown in Fig.6, for sterilization of the drug without the transfer of the drug from stable state to unstable state.

In particular, figure 6 shows a plot of the pressure and temperature from the time, according to which the pharmaceutical product is subjected to a pressure of approximately 700 MPa, bring energy to raise the temperature to about 121°C for a period in the first cycle, followed by a second cycle of pressure reduction to atmospheric pressure and the temperature is reduced to room temperature over a certain period. Figure 6 shows that the drug undergoes rapid temperature changes during each pressure pulse. These temperature changes cause the instantaneous adiabatic heating and cooling products, respectively p and the compression and release of pressure. Typical values of time to ensure sterility are of the order of minutes, while they conduct at least 2 cycles.

Pharmaceutical drug is considered to be sterilized when the probability of non-sterile sample of the product is equal to or below one million. This condition satisfies the requirements of the pharmacopoeias of the United States, Europe and Japan.

VIII. Mortality for sterilization method

Above 1% nanosuspension Itraconazole processed through a sterilization cycle, the high pressure, check for sterility. The impact of sterilization under high pressure in physiological solution on mortality of bacteria Bacillus stearothermophilus has already been shown (using the most heat-resistant strain, referred to as demonstrating a high resistance to steaming at their vinagrette - see ANSI/AAMI/ISO 11134-1993, Sterilization of health care products - Requirements for validation and routine control - Industrial moist heat sterilization. American national standard developed by the Association for the advancement of medical instrumentation and approved by the American national standards Institute, p.12, section A.6.6.). The test and control samples with sowing in at least one million spores of the bacteria Bacillus stearothermophilus, subjected to processing in two different ways, the first method used the pressure OK the lo 600 MPa for 1 minute and the second method used a pressure of about 600 MPa for six 10-second cycles. The initial and maximum temperatures in both ways were 90 and 121°C, respectively. In both ways there was no surviving organisms in physiological solutions (see table 1). It is expected that similar results will be revealed when infect and sterilized 1% nanosuspension Itraconazole.

Table 1
Mortality of bacteria Bacillus stearothermophilus using two methods of sterilization under high pressure
SolutionThe mode of sterilizationCFU/ml
Physiological solution of 1 - controlWithout sterilizationof 1.9×106
Physiological solution of 1 - sterilisable600 MPa, one 1-minute cycle, initial temperature = 90°C, the temperature at high pressure = 121°C0
Saline 2 - controlWithout sterilization3.7 x 106
Physiological solution of 2 - sterilisable 600 MPa, six 10-second cycles, initial temperature = 90°C, the temperature at high pressure = 121°C0

IX. Containers

A variety of containers, preferably used as a medical device (e.g., for pharmaceutical injection, renal dialysis and capture/processing of blood), can be sterilized by methods of the present invention. Examples of these containers include, but without limitation, the following, the sets for the introduction of fluid (including sets with syringes), devices for blood collection (for example, packaging for blood), disposable device for automated processing of blood dialysis apparatus, and bags, catheters and devices for peritoneal dialysis. Typically these systems will contain an element (e.g., flexible tubing) for pumping fluid.

Figure 11 presents the container 150 for free flowing materials with two side walls 152, bounding between a camera 154. Element 155 to access sterile access to the contents of the container. On Fig shows a multi-chamber container 160 containing the first and second chambers 162, 164, United detachable seal 166. Data multi-chamber containers are especially suitable for storage of fluid in one chamber and the powder in the second chamber or the fluid in both the ameres. Detachable seal provides the components are mixed immediately before use. Suitable multi-chamber containers include, but without limitation, the following, the containers described in U.S. patent No. 5577369, 6017598, which is incorporated into this description by reference and are a part of it. The method according to claim 1, wherein the container is selected from the group consisting of a container that is impermeable to fluid, syringe and sealed elastic tube.

In a preferred embodiment of the invention the side walls are made of a polymer that does not contain PVC. The side walls may be made of a single layer structure 170 (Fig) or multilayer structure 171 with the first and second layers 172, 174, as shown in Fig. It is assumed that the film may contain more than 2 layers. In another embodiment of the invention the side walls are oriented and are not supposed to heat-shrinkable films.

Suitable polymers that do not contain PVC, to perform the side walls include polyolefins, copolymers of ethylene and lower alkylacrylate, copolymers of ethylene and lower alkyl substituted alkylacrylate, copolymers of ethylene and vinyl acetate, polybutadienes, polyesters, polyamides and copolymers of styrene and hydrocarbon.

Suitable polyolefins include homopolymer and copolymers, obtained by polymerization of alpha-olefins containing from 2 to 20 carbon atoms, and preferably from 2 to 10 carbon atoms. Therefore, suitable polyolefins include polymers and copolymers of propylene, ethylene, butene-1, pentene-1, 4-methyl-1-pentene, hexene-1, Heptene-1, octene-1, nonene-1 and mission-1. In the most preferred embodiment, the polyolefin is a homopolymer or a propylene copolymer or a homopolymer or copolymer of polyethylene.

Suitable homopolymers of polypropylene can be characterized by the stereochemistry of amorphous isotactic, syndiotactic, atactic, polisomaticheskoi or stereoblock. In one preferred embodiment, the invention is a homopolymer polypropylene obtained by using a catalyst with a single center of polymerization.

Suitable propylene copolymers produced by polymerization of propylene monomer with an α-olefin containing from 2 to 20 carbon atoms. In a more preferred variant of the invention, the propylene will copolymerized with ethylene in a mass ratio of from about 1% to about 20%, preferably from about 1% to about 10% and most preferably from 2% to about 5% by weight of the copolymer. Copolymers of propylene and ethylene may be a statistical or block the SOP is the materials. In a preferred variant of the invention, the propylene copolymer is obtained using a catalyst with a single center of polymerization.

You can also use a mixture of copolymers of polypropylene and α-olefin, in which the propylene copolymers may vary according to the number of carbon atoms in α-olefin. For example, the present invention is assumed to be a mixture of copolymers of polypropylene and α-olefin, in which the copolymer contains α-olefin with 2 carbon atoms and the other copolymer contains α-olefin with 4 carbon atoms. You can also use any combination of α-olefins with 2 to 20 carbon atoms, and preferably from 2-8 carbon atoms. Accordingly, the present invention is assumed to be a mixture of copolymers of polypropylene and α-olefin, in which the first and second α-olefins contain carbon atoms in the following quantitative combinations: 2 and 6, 2 and 8, 4 and 6, 4 and 8. It also assumes the use of more than 2 copolymers of polypropylene and α-olefin in the mixture. Suitable polymers can be obtained using the Catalloy process.

Perhaps it would be advisable to use polypropylene with high melt strength. Polypropylene with high melt strength can be a homopolymer or a copolymer of polypropylene with a melt flow index in the range from 10 grammo the/10 min to 800 grams/10 min, preferably from 30 g/10 min to 200 grams/10 minutes, or any range or combination within the above ranges. It is known that polypropylene with high strength melt contain branching with the formation of the long side-chain and the free ends in propylene molecules. Methods of preparation of polypropylene, which are characterized by high melt strength, as described in U.S. patent No. 4916198, 5047485 and 5605936, which is incorporated into this description by reference and made a part hereof. One such method is that irradiate the linear propylene polymer in an environment in which the concentration of active oxygen is approximately equal to 15% by volume, radiation with high energy ionization dose 1-104megarad per minute over a period of time sufficient to cause a significant number of breaks chains in the linear propylene polymer but insufficient to material became gel-like. Irradiation leads to breaks in the chain. The subsequent recombination of the fragments of the chains leads to the formation of new circuits, as well as to the connection of fragments of chains in the chain with the formation of branches. The above advanced results in the desired high-molecular non-linear propylene polymer material with branches, with the formation of long side chain and free the ends. Irradiation deliver up until not formed a significant amount of long chain branching. The material is then processed for decontamination, essentially all free radicals present in the irradiated material.

Polypropylene with high melt strength can also be obtained as described in U.S. patent No. 5416169, which is fully incorporated into the present description by reference and is a part of it, when the specified organic peroxide (di-2-ethylhexylcarbonate) is subjected to interaction with polypropylene in given conditions, and then the melt is stirred. These polypropylene represent a linear crystalline polypropylene with branching factor essentially equal to 1, and therefore do not contain branches with the formation of long side chains and loose ends and will have the true viscosity of from about 2.5 DL/g to 10 DL/g

Suitable homopolymers of ethylene include homopolymers with density above 0,915 g/cm3which include low density polyethylene (LDPE), medium density polyethylene (MDPE) and high density polyethylene (HDPE).

Suitable copolymers of ethylene produced by polymerization of ethylene monomers with an α-olefin containing 3 to 20 carbon atoms, preferably 3-10 carbon atoms and most preferably 4-8 and the Ohm carbon. It is also advisable to copolymers of ethylene had a density according to the measurements according to ASTM D-792, a minimum of approximately 0,915 g/cm3and preferably less than about 0.910 g/cm3and more preferably less than approximately to 0.900 g/cm3. These polymers often referred to as VLDPE (polyethylene, very low density) or ULDPE (polyethylene low density). In a preferred embodiment, the copolymers of ethylene and α-olefins is obtained using catalyst with a single center of polymerization and preferred systems of metallocene catalysts. It is believed that catalysts with a single center of polymerization are characterized by a single, spatial and electron-equivalent position of the catalytically active center unlike type catalysts Ziegler-Natta, which are known to contain a mixed composition of the centers of polymerization. Such a copolymer of ethylene and α-olefin, catalyzed by similar centers are being sold by the company Dow under the trade name AFFINITY, by DuPont Dow under the trade name ENGAGE®and company Exxon under the trade name EXACT. These copolymers are sometimes labeled m-ULDPE in the present description.

Suitable copolymers of ethylene also include copolymers of ethylene and lower alkylacrylate, copolymers of ethylene and lower alkyl-substituted alkylacrylate and copolymers of ethylene and vinyl acetate with a vinyl acetate content from about 8% to about 40% by weight of the copolymer. The term "lower alkylacrylate" refers to the comonomers with the formula presented in figure 1:

Scheme 1

R denotes alkali containing 1-17 carbon atoms. Therefore, the term "lower alkylacrylate" includes, but without limitation, the following, methyl acrylate, acrylate, butyl acrylate, etc.

The term "lower alkyl-substituted alkylacrylate" refers to the comonomers with the formula presented in figure 2:

Scheme 2

R1and R2denote alkali containing 1-17 carbon atoms, which may contain the same number of carbon atoms or a different number of carbon atoms. Therefore, the term "lower alkyl-substituted alkylacrylate" includes, but without limitation, the following, methyl methacrylate, ethyl methacrylate, metilmetakrilat, tilatequila, butylmethacrylate, butylacrylate etc.

Suitable polybutadienes include 1,2 - and 1,4-additive products of 1,3-butadiene (these products are collectively referred to as polybutadienes). In a more preferred embodiment of the invention the polymer is a 1,2-additive product of 1,3-butadiene (these products are collectively referred to as "1,2-polybutadienes"). In an even more preferred embodiment of the invention representing the th interest polymer is syndiotactic 1,2-polybutadiene and even more preferably syndiotactic 1,2-polybutadiene with a low degree of crystallinity. In an even more preferred embodiment of the invention syndiotactic 1,2-polybutadiene with a low degree of crystallinity will have a crystallinity of less than 50%, preferably below about 45%, more preferably below about 40%, even more preferably the degree of crystallinity is in the range from approximately 13% to approximately 40% and in the most preferred embodiment, from about 15% to about 30%. In a preferred embodiment of the invention syndiotactic 1,2-polybutadiene with a low degree of crystallinity will have a melting point according to the measurements according to ASTM D 3418, from about 70°C to about 120°C. Suitable resins include resins sold by JSR (Japan Synthetic Rubber) under the designations of marks: JSR RB 810, JSR RB 820 and JSR RB 830.

Suitable polyester resins include polycondensation products of di - or polycarboxylic acids and di - or polyhydric alcohols or oxides alkylene. In a preferred embodiment of the invention a complex polyester is a polyester alkoxylate. Suitable polyesters of alkoxysilane derived from the interaction of 1,4-cyclohexanedimethanol, 1,4-cyclohexanedicarboxylic acid and polytetramethylene simple ether and collectively, are referred to abbrevi is dependent on the PCCE. Suitable PCCE sold by the company Eastman under the trade name ECDEL. Suitable polyesters optionally include elastomers with a complex of the polyester chains, which are block copolymers of crystalline segment of polybutylene terephthalate and a second segment of a soft (amorphous) glycols with a simple polyester chains. These elastomers with a complex of the polyester chains are sold by the company Du Pont Chemical Company under the trade name HYTREL®.

Suitable polyamides include the polyamides, which are formed as a result of interaction with the ring opening of lactams with 4-12 carbon atoms. Therefore, this group of polyamides include nylon 6, nylon 10, and nylon 12. Suitable polyamides include aliphatic polyamides resulting from the condensation reaction of diamines with 2-13 carbon atoms, aliphatic polyamides resulting from the condensation reaction of dibasic acids with 2-13 carbon atoms, aliphatic polyamides resulting from the condensation reaction of dimeric fatty acids and amides containing copolymers. Therefore, suitable aliphatic polyamides include, for example, nylon 6,6, nylon 6,10 and polyamides dimeric fatty acids.

The styrene copolymer of styrene and hydrocarbon includes article is rol and various substituted styrene, including alkyl-substituted styrene and halogen-substituted styrene. An alkyl group can contain from 1 to about 6 carbon atoms. Specific examples of substituted styrene include alpha methylsterol, beta methylsterol, vinyltoluene, 3-methylsterol, 4-methylsterol, 4-isopropylthio, 2,4-dimethylstyrene, o-chloresterol, p-chloresterol, o-Postira, 2-chloro-4-methylsterol etc. Most preferred is styrene.

Hydrocarbon plot of a copolymer of styrene and hydrocarbon includes diene with conjugated double bonds. Diene with conjugated double bonds, which can be used are compounds containing from 4 to about 10 carbon atoms and, more generally, from 4 to 6 carbon atoms. Examples include 1,3-butadiene, 2-methyl-1,3-butadiene (isoprene), 2,3-dimethyl-1,3-butadiene, chloroprene, 1,3-pentadiene, 1,3-hexadiene etc. you Can also use a mixture of these dienes with conjugated double bonds, for example, a mixture of butadiene and isoprene. Preferred diene with conjugated double bonds are isoprene and 1,3-butadiene.

Copolymers of styrene and hydrocarbon can be block copolymers, including double, triple, multi, star block copolymers, and mixtures thereof. Specific examples of the double block copolymers include STI is ol-butadiene, styrene-isoprene and their hydrogenated derivatives. Examples of ternary block copolymers include styrene-butadiene-styrene, styrene-isoprene-styrene, alpha-methylsterol-butadiene-alpha-methylsterol and alpha methylsterol-isoprene-alpha methylsterol and their hydrogenated derivatives.

Selective hydrogenation of the above-mentioned block copolymers can be made using a variety of well known methods including hydrogenation in the presence of such catalysts as Nickel Raney catalyst, the catalysts of the group of noble metals, e.g. platinum, palladium, etc. and soluble catalysts for transition metals. Suitable methods of hydrogenation, which can be used are the ways in which containing the diene polymer or copolymer is dissolved in an inert hydrocarbon diluent such as cyclohexane, and hydronaut by reacting with hydrogen in the presence of a soluble hydrogenation catalyst. This method is described in U.S. patent No. 3113986 and 4226952 described in the present description by reference and are a part of it.

Especially useful gidrirovanie block copolymers are hydrogenated block copolymers of the type styrene-isoprene-styrene, such as a block copolymer-type styrene-(ethylene/propylene)-styrene. When hydronaut block copolymer type polystyrene-p is libautodie-polystyrene, the resulting product resembles a copolymer with a regular distribution of units of ethylene and 1-butene (EB). As explained above, when applied with conjugated diene double bonds represents isoprene, the resulting hydrogenated product recalls copolymer with a regular distribution of units of ethylene and propylene (EP). One example of a commercially available selectively hydrogenated product is KRATON G-1652, which is a hydrogenated triple-a block copolymer type SBS (styrene-butadiene-styrene)containing 30% of end parts of styrene, and the equivalent of middle management is a copolymer of ethylene and 1-butene (EB). This hydrogenated block copolymer is often denoted by the acronym SEBS. Kraton G-1657 is a mixture of the ternary block copolymer-type SEBS and double block copolymer SBS type, which is also appropriate. Other suitable copolymers of the type SEBS or SIS sold by the company Kurary under the trade names SEPTON®and HYBRAR®.

In addition, it may be appropriate to use grafted modified block copolymers of styrene and hydrocarbon by the reaction of grafting reagent based on unsaturated monocarboxylic or dicarboxylic acid with an alpha, beta-structure in the above-described selectively hydrogenated block copolymers.

Block-copolyme the s diene with conjugated double bonds and vinyl aromatic compounds impart a reagent based on unsaturated monocarboxylic or dicarboxylic acid with an alpha, beta-structure. Reagents based on carboxylic acids include carboxylic acids themselves and their functional derivatives, for example, anhydrides, imides, metal salts, esters, etc. that are capable of vaccination on the selectively hydrogenated block copolymers. The grafted polymer will typically contain from about 0.1 to about 20% and preferably from about 0.1 to about 10% by weight of the total weight of the block copolymer and the reagent on the basis of the carboxylic acid type grafted carboxylic acid. Specific examples of suitable monobasic carboxylic acids include acrylic acid, methacrylic acid, phenylacrylate acid, cretonne easy acid, anhydride of acrylic acid, sodium acrylate, calcium acrylate and acrylate magnesium, etc. are Examples of dicarboxylic acids and their suitable derivatives include maleic acid, maleic anhydride, fumaric acid, metaconule acid, taconova acid, citraconate acid, itacademy anhydride, citraconic anhydride, monometallic, mononitriles etc.

A block copolymer of styrene and hydrocarbon can be modified oil, for example, modified SEBS oil, sold by Shell Chemical Company under the trademark KRATON G2705.

It is also expected that films can be made from a mixture of wiseup is mentioned polymer components. Particularly suitable mixtures of the polymers described in U.S. patent No. 5849843, which is included in the present description by reference and is part of it. In a preferred embodiment of the invention, one layer is made of a compound containing at least 2 components, or preferably at least three components. These blends of polymers can form a single-layer film or may be combined in a multilayer film, as described in U.S. patent No. 5998019, which is included in the present description by reference and is part of it.

Three-component composition

In the first embodiment, three-component system, the first component will be to inform the resistance and flexibility of the composition. This component can be selected from the group consisting of amorphous polyalpha-olefins, and preferably is a flexible polyolefin. These polyolefins should be resistant to deformation at high temperatures up to 121°C, to have a maximum melting point above 130°C and high flexibility, the module is not more than 40,000 pounds per square inch and preferably not more than 20,000 pounds per square inch. In addition, some polypropylene high syndiotactic also characterized by a high melting point and low modulus. The content of the first component should be in the range of 40-90% by weight of the composition.

The second component of the three-component composition is a RF (radiochastotnoi) sensitive polymer, which tells the compositions ability to RF-welding and can be selected in either of the two groups of polar polymers. The first group consists of ethylene copolymers containing 50-85% of ethylene with comonomers selected from the group consisting of acrylic acid, methacrylic acid, esters derived from acrylic acid with alcohols containing 1 to 10 carbon atoms, esters derived from methacrylic acid with alcohols containing 1 to 10 carbon atoms, vinyl acetate and vinyl alcohol. RF-sensitive polymer can be selected from a second group consisting of polymers containing segments of polyurethane, complex, polyester, polyurea, polyimide, polysulfones and polyamides. Data functionalityand patterns can be 5-100% RF-sensitive polymer. RF-sensitive polymer should be 5-50% by weight of the composition.

In the preferred embodiment, RF-sensitive component is represented by a copolymer of ethylene and methyl acrylate content of methyl acrylate in the range of 15-25% by weight of the polymer. The final component of the three-component connection provides compatibility between the first two components and is selected from styrene block copolymers which preferably contains a functional group is maleic anhydride. The third component should be 5-30% by weight of the composition.

In the second embodiment, a three-part film of the first component reports the composition of the ability of RF-welding and flexibility in a given temperature range. The first component reports the temperature ("heat-resistant polymer and selected from the group consisting of polyamides, polymides, polyurethanes, polypropylene and polymethylpentene. In a preferred embodiment, the first component comprises 30-60% by weight of the composition and preferably consists of polypropylene. The second component reports the ability of RF-welding and flexibility in a given temperature interval. RF-polymer selected from the above-described first and second groups, with the exception of the ethylene-vinyl alcohol. The second component should be 30-60% by weight of the composition. The third component provides compatibility between the first two components selected from block copolymers of the type SEBS and preferably contains a functional group is maleic anhydride. The third component should be 5-30% by weight of the composition.

Four songs

The first component of a four-part film is intended for a message of resistance. This component may be selected from polyolefins, preferably, polypropylene and, in particular, the acceptance of the ski copolymers of propylene and alpha-olefins (PPE). In a preferred embodiment, the molecular weight of the PPE will be restricted to a narrow interval. PPE possess the necessary rigidity and resistance to plastic deformation at temperatures of autoclaving about 121°C. However, by themselves PPE are too hard to meet the requirements for flexibility. When combining the mixture with some polymers with low module can provide high flexibility. Examples of suitable PPE include the products sold under the name Soltex 4208 and Exxon Escorene PD9272. These copolymers with low module may include copolymers based on ethylene, for example, a copolymer of ethylene and vinyl acetate ("EVA"), copolymers of ethylene and alpha-olefins or the so-called polyethylene of low density (typically less than 0.90 kg/l) ("ULDPE"). Data ULDPE include commercially available products sold under the trademark TAFMER®(Mitsui Petrochemical Co.) with the designation of the A485, Exact®(Exxon Chemical Company) with the designation 4023-4024, polymers technology Insite®(Dow Chemical Co.). In addition, it was found that suitable copolymers of polybutene-1 ("PB"), for example, copolymers sold by Shell Chemical Company under the designation PB-8010, PB-8310; thermoplastic elastomers based on block copolymers of the type SEBS (Shell Chemical Company), polyisobutylene ("PIB") designation Vistanex L-80, L-100, L-120, L-140 (Exxon Chemical Company), copolym the market of etilenvinilatsetata, of methyl acrylate ("EMA"), for example, copolymers with name EMAC 2707 and DS-1130 (Chevron), and n-butylacrylate ("ENBA") (Quantum Chemical). Copolymers of ethylene, for example, copolymers of acrylic and methacrylic acids and their partially neutralized salts and ionomers, e.g., PRIMACOR®(Dow Chemical Company) and SURYLN®(E.I.DuPont de Nemours & Company) also met the requirements.

Typically, the copolymers of ethylene with a melting temperature below about 110°C not suitable for autoclaving. In addition, only in limited ranges of each component simultaneous fulfillment of the requirements for flexibility and reused. In a preferred embodiment, the first component is chosen from the group of Homo - and random copolymers of polypropylene with alpha-olefins, which comprise about 30-60%, preferably 35-45%, and preferably 45% by weight of the composition. For example, as a first component, the preferred random copolymers of propylene with ethylene in which the ethylene content is in the range of 1-6%, and preferably 2-4% by weight of the polymer.

The second component of four-component of the composition gives the flexibility and ductility at low temperature and is the second polyolefin other than the polyolefin of the first component, while the aforementioned second polyolefin not contains traumas parts of polypropylene (polyolefin is not based on propylene"). Preferably he presents copolymers of ethylene, including ULDPE, polybutene, copolymers of butene and ethylene, ethylene vinyl acetate, copolymers with vinyl acetate content in the range of about 18-50%, copolymers of ethylene and methyl acrylate content of methyl acrylate in the range of about 20-40%, copolymers of ethylene and n-butyl acrylate content of n-butyl acrylate in the range of 20-40%, copolymers of ethylene and acrylic acid with a content of acrylic acid above about 15%. Mentioned products are sold, for example, under such designations as Tafmer A-4085 (Mitsui), EMAC DS-1130 (Chevron), Exact 4023, 4024 and 4028 (Exxon), and should be approximately 25-50%, preferably 35-45%, and most preferably 45% by weight of the composition. To make a four-part composition abilities to RF-dielectric losses in the composition include some well-known ingredients with high dielectric losses ("RF-sensitive polymers"). These polymers can be selected from the group RF-polymers in the above-described first and second groups.

Other RF-active materials include PVC, vinylidenechloride and fluoride, copolymer of bis-phenol-A and epichlorhydrin known as PHENOXYS®(Union Carbide). However, the significant content of the chlorine - and fluorine-containing polymers produces undesirable composition, as the burning of this material has led the ILO to the formation of inorganic acids.

Polyamides RF-sensitive polymer is preferably selected from aliphatic polyamides resulting from the condensation reaction of diamines with 2-13 carbon atoms, aliphatic polyamides resulting from the condensation reaction of dibasic acids with 2-13 carbon atoms, polyamides resulting from the condensation reaction of dimeric fatty acids and containing amides (statistical, block and graft) copolymers. Polyamides, such as nylon, are widely used in thin film materials, as they provide the strength of the film resistance. However, nylon is rarely used in the layer which is in contact with medical solutions, because they usually contaminate the solution from leaching into the solution. The preferred RF-sensitive polymers are a variety of polyamides from dimeric fatty acids, sold by Henkel Corporation under the designations MACROMELT and VERSAMID that do not lead to such contamination. RF-sensitive polymer preferably should be approximately 5-30%, preferably 7-13% and preferably 10% by weight of the composition.

The fourth component of the composition gives the compatibility between the polar and nonpolar components of the composition (sometimes referred to as "combining the polymer and preferably presents styrene b is OK-copolymers with soft carbon segments. In a more preferred embodiment, the fourth component selected from block copolymers of the type SEBS, which modify the functional groups of maleic anhydride, epoxy or carboxylate functional groups, and preferably is a block copolymer type SEBS, which contains a functional group of maleic anhydride ("functionalized"). This product is sold by the company Shell Chemical Company under the designation KRATON RP-6509. Combining the polymer should be about 5-40%, preferably 7-13% and preferably 10% by weight of the composition. Maybe it is also advisable to add a fifth component of the block copolymer type SEBS not containing functional groups, for example, block copolymers sold by Shell Chemical Company under the designations KRATON G-1652 and G-1657. The fifth component should be approximately 5-40%, preferably 7-13% or more by weight of the composition.

For each of the above compositions, you may need to enter, in small quantities, other additives, for example additives reduce friction, lubricants, waxes and substances that prevent adhesion, to the extent necessary and as is well known in this field until the final composition will not perform the above-described requirements for physical properties.

The film can be performed with use of the cation technologies, widely known in the industry. For example, the above components can be mixed in dry form in a high-intensity mixer, for example, Welex mixer and feeding into the extruder. Components can also be submitted under the action of gravity in the high-intensity mixer-extruder twin screw design, for example, Werner Pfleiderer, and outgoing product may be used in multiple threads in a water bath, pelletized and dried for use. Step granulation can be excluded in the third method, the supply of the output product of the extrusion mixer directly into the extruder film. You can also embed a section of high-intensity mixing in the extruder film to film alloy could produce with a single extruder.

In the multilayer film 171 can use the above mixture as a single layer 172 and another layer 174. In one of the preferred embodiments of the invention the layer 174 is an outer layer. The outer layer 174 reported resistance to deformation at high temperatures and resistance to abrasion and preferably consists of polypropylene and is preferably a copolymer of polypropylene mixed with a block copolymer of styrene and hydrocarbon. In a more preferred embodiment, the outer layer 174 is a copolymer in which propylene, mixed with the block copolymer type SEBS in a proportion of 0-20% by weight. The thickness of the outer layer 174 must be in the range of 0.2 to 3.0 mils.

On Fig shows another variant implementation of the present invention, containing the core layer 176 located between the outer layer 172 and RF-sensitive layer PA. The core layer 176 reported resistance to deformation at high temperatures and flexibility of the film structure 171 and the compatibility between the components of the film structure 171. In a preferred embodiment, the core layer will have a thickness in the range of 0.5 to 10 mils and preferably 1-4 mils. The core layer 176 has three components. The first component is a polyolefin and preferably polypropylene in an amount which is 20-60% by weight of the core layer 176, preferably 35-50%, and most preferably 45% of the core layer 176.

The second core component layer 176 are selected from the group consisting of compounds that tell the flexibility of the core layer 176, including ULDPE, copolymers of polybutene. The second component of the core layer is preferably ULDPE or polybutene-1 with a mass content of 40-60% preferably 40-50%, and most preferably 40%.

The third component of the core layer 176 is selected from the group of compounds that impart compatibility m is waiting for other components of the core layer 176, and contains the block copolymers of styrene and hydrocarbon and in the most preferred embodiment, the block copolymers of the type SEBS. The third component is contained in a proportion preferably in the range of 5-40% by weight of the core layer 176, preferably 7-15% and most preferably 15%.

You can also enter the fourth component of the core layer 176, re razmeshcheny edged material, utilized during the manufacture of the containers. Cut the material distributed over the core layer 176. Scraps can be added in a proportion of preferably approximately in the range 0-50% by weight of the core layer 176, preferably in the range of 10-30% and most preferably in the range 3-12%.

On Fig presents film 180 containing layer 182 contact with the solution, coupled with the side of the RF-sensitive layer 172, the opposite outer layer 174. Layer 182 contact with the solution may be made of one of the aforementioned materials, in the preferred embodiment will contain a polyolefin and more preferably will be of the same material as the outer layer 174, or the same material as the core layer 176. Layer 182 contact with the solution has a thickness preferably in the range of 0.2 to 1.0 mils and most preferably of 1.0 mil.

On Fig shows another variant of implementation of the multilayer film design, the functions, containing outer layer 174, the core layer 176 and RF-sensitive layer 172, as described above, with an additional separate layer of trimmings 190 between the outer layer 174 and the core layer 176. On Fig presented in a separate layer from the trimmings 190 between the core layer 176 and RF-sensitive layer 172. On Fig depicts a layer of trimmings 190, separating the core layer 176 on the first and second core layers a and 176b. Layer trimmings 190 should be of a thickness preferably in the range of 0.5 to 5.0 mils and most preferably of 1.0 mil.

On Fig shows another variant implementation of the present invention, containing six layers, including outer 174, core 176 and RF-sensitive layers 172 described above, a barrier layer 200 disposed between the core 176 and RF-sensitive layers 172 and coupled with them connecting layers 202, attached to opposite sides of the barrier layer 200. On Fig shows the barrier layer 200 between the core layer 176 and the outer layer 174. On Fig shows the barrier layer 200 that separates the core layer 176 on two core layers 176a and 176b. The barrier layer 200 increases the gas impermeability film design. The barrier layer 200 are selected from the group consisting of ethylene vinyl alcohols, for example, that sold under the name Evalca (Evalca Co.), polyamide with a high degree of vitreous is ti or crystallinity, for example, Sclar PA®(Dupont Chemical Co.), copolymers of Acrylonitrile with a high content nitrile, such as Barex®sold by British Petroleum. In a preferred embodiment, the barrier layer 200 is an ethylene vinyl alcohol and has a thickness in the range of 0.3 to 1.5 mils and most preferably of 1.0 mil.

Binder layers 202 can be selected from modified copolymers of ethylene and propylene, for example, products sold under the designation Prexar (Quantum Chemical Co.) and Bynel (Dupont), and should have a thickness in the range of 0.2 to 1.0 mils and most preferably 0.5 mil.

Sterilization under high pressure according to the present invention is also suitable for the sterilization of empty drainage bags for CAPD (chronic ambulatory peritoneal) dialysis, for example, the container described in U.S. patent No. 6004636, which is included in the present description by reference and is part of it. Other containers suitable for final sterilization using technologies sterilization under high pressure according to the present invention, includes a flexible container for cell culture, for example, the containers described in U.S. patent No. 5935847, 4417753, 4210686, which is entirely included in the present description by reference and constitute a part of him. Compatible with protein films and containers, such notoriuosly in U.S. patent No. 6309723, which is included in the present description by reference and is a part of, also can be sterilized using the proposed technologies sterilization under high pressure according to the present description. In addition, sterilization is also suitable for the sterilization of containers for the content of the oxygen-sensitive compounds, for example, deoxyhemoglobin, for example, the container described in U.S. patent No. 6271351, which is included in the present description by reference and is part of it. Because sterilization require that mentioned the containers were exposed only briefly to temperatures exceeding 100°C, many containers that are not suitable for final sterilization using standard technologies steaming container at a temperature of 121°C for 1 hour, can be subjected to a final sterilization technology high pressure according to the present invention.

On Fig shows the syringe 220, with cylinder plunger 222 and 224, which are widely known in this field. The syringe 220 can be made of the above materials. The cylinder of the syringe can be filled with one of the dispersions or dry powder pharmaceutical compounds and then autoclaved as described above. The cylinder of the syringe, and preferably both the cylinder and the plunger should the s to be able to change the volume when the pressure increases, and both parts 222 and 224 must have sufficient resistance to deformation at high temperatures to withstand the way to the final sterilization of the present invention.

On Fig shows the cartridge 230 or insert with the housing 232, forming a chamber 234. The chamber 234 is sealed by end cap 236 or a pair of end caps, if necessary. The cartridge can be inserted into the device for introduction of, for example, a needleless syringe, for example, the device described in U.S. patent No. 6132395, or other device for the introduction, which is able to access the contents of a chamber 234 and to deliver the content for use.

On Fig shows the device 250 for entry of fluid from a medical elastic tube device 252 and 254 access. The access device may be subject to puncturing element 154 access or can be made with the possibility of coupling or other connection to the cylinder 222 of the syringe to transport the fluid from the container used for sterilization, to make the introduction of the patient or for delivery to another device, used for the introduction of the composition to the patient.

There are many containers, for example, some medical polymer containers that can't stand the way the final sterilized by steaming container at 121°C in those which begins 1 hour.

X. Products

The present invention provides a sterilized product, and preferably with pharmaceutical drugs, including, but without limitation, containers containing sterile pharmaceutical preparations and preparations sterilized by summing up the heat to the product and the pressure at the product up to a pressure higher than 0.25 MPa. The present invention also provides a sterile pharmaceutical products that do not contain modifiers cloud point.

It should be understood that the specialists in this field will become apparent, various changes and modifications listed in the description of the preferred embodiments. These changes and modifications can be made without going beyond the nature and scope of the present invention and without diminishing the intended benefits. Therefore, it is assumed that these changes and modifications are covered by the attached claims.

1. The sterilization method of dynamic dispersion system having a stable state and an unstable state, the method includes the following stages:
the impact on the dispersion system of small particles or droplets pressure higher than 0.25 MPa to raise the temperature of the system to temperatures above 100°C for a period of time sufficient to ensure STERI the major system, where the dispersion system includes a dispersion of micro - and nanoparticles in the form of small particles or droplets; the system of small particles or droplets has a stable state and an unstable state; and
removing pressure from the dispersion system of small particles or drops before the system of particles or droplets becomes unstable state, where the particles or droplets include (i) a pharmaceutically active compound and (ii) excipient, excipient associated with a pharmaceutically active compound, and excipient includes surface-active substance.

2. The method according to claim 1, in which stage the pressure increases the temperature of the system to temperatures above 120°C.

3. The method according to claim 1, in which stage of pressure on the system is a pulse.

4. The method according to claim 1, in which the dynamic system further comprises a carrier.

5. The method according to claim 1, in which sterility is set when the likelihood of an open system is equal to or less than one millionth.

6. The method according to claim 4, in which the carrier is an aqueous solution, organic solvent or oil.

7. The method according to claim 1, in which the particles or droplets have an average effective particle size of less than 100 microns.

8. The method according to claim 1, in which the particles or droplets have an average effective particle size of less than 10 microns.

9. The method according to the .1, in which particles or droplets have an average effective particle size of less than 7 microns.

10. The method according to claim 1, in which the particles or droplets have an average effective particle size of less than 3 microns.

11. The method according to claim 1, in which the particles or droplets have an average effective particle size of less than 1 micron.

12. The method according to claim 11, in which particles or droplets have an average effective particle size of less than 500 nm.

13. The method according to claim 1, in which excipient associated with the particle or drop by the method selected from the group consisting of a covalent bond with them, ionic bond with them, electronic attraction to him, the adsorption is carried on the surface and the suspension in them.

14. The method according to claim 1, in which the surfactant is selected from the group consisting of at least one anionic, cationogenic, nonionic and zwitterionic surfactants and biological surface-active molecules.

15. The method according to claim 1, comprising the additional step of applying heat to the system additional heating.

16. The method according to item 15, in which the temperature increases above 100°C for a period of time more than 1 minute

17. The method according to clause 16, in which the pressure on the system to provide pulses of varying pressure.

18. The method according to claim 1, further comprising providing a polymeric container containing m is small particles or droplets, including pharmaceutically active compound, where the small particles or droplets dispersed in sterile media.

19. The method according to p, in which the polymeric container is made of material that does not contain polyvinyl chloride.

20. The method according to p, in which the container is made from a film having a single layer structure or a multilayer structure.

21. The method according to p, in which the container is made of polymers.

22. The method according to p, in which the polymeric container is arranged to be connected to the element for pumping a fluid medium.

23. The method according to item 22, in which the element for pumping a fluid medium is an elastic tube.

24. The method according to item 22, in which the element for pumping a fluid medium is a kit for introducing a fluid medium.

25. The method according to p, in which the container is selected from the group consisting of a container that is impermeable to fluid, syringe and sealed elastic tube.

26. The method according to p, where the polymeric container includes opposite side walls, and the walls have a modulus of elasticity less than about 275,8 MPa (40,000 psi).

27. The method according to claim 1, where the variance based on water based mud.

28. The method according to p, in which the type of container selected from the group consisting of a container for intravenous infusion, drainage m is the Cabinet, multi-chamber container that is compatible with the protein container, container for cell culture container for a blood substitute, cartridge device for introduction, the cylinder of the syringe and a kit for introducing a fluid medium.

29. The method according to claim 1, where the size distribution of particles or droplets remain constant at the specified sterilization method.

30. The method according to claim 1 where the pharmaceutically active compound is slightly soluble in water.

31. The method according to item 30, where the pharmaceutically active compound has a solubility in water below about 10 mg/ml

32. Medical device containing
a flexible polymeric container that is impermeable to fluid containing sterile pharmaceutical compound, sterilized by the method according to claim 1, and dispersed in aqueous solution, while the connection is in the form of particles with an average size of less than 1 μm, and excipient associated with particles, where the solution essentially does not contain modifiers cloud point.

33. Product by p, in which the container is made of material that does not contain polyvinyl chloride.

34. Product by p, in which the container is made from a film having a single layer structure or a multilayer structure.

35. Product by p, in which the film contains more than 50 wt.% polyolefin.

36. Product by p in which the prisoner is and capable of sealing in a container using technologies such as radio frequency welding.

37. Product by p, in which the film has a modulus of elasticity less than 275,8 MPa (40,000 psi) when measured according to ASTM D-882.



 

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1 dwg, 1 tbl

FIELD: space medicine.

SUBSTANCE: method comprises sampling the agent accumulated by filters of the ventilation system and manual vacuum cleaners, sending the samples to the ground, and setting the specimens on a feeding agent.

EFFECT: enhanced reliability.

FIELD: disinfecting of products.

SUBSTANCE: disinfecting and/or warming device has vapor unit for eliminating microorganisms at surface of solid product, in particular, solid food product. Vapor unit has at least one passage for vapor and opening being adjacent to cavity where water vapor jet is applied under pressure through passage for vapor. Water vapor released from opening, is driven into oscillation at frequency, preferably sonic frequency, determined by cavity. Vapor unit has external part, internal wall of which par defines external wall to let vapor in, and internal part, which forms external wall of passage for vapor and limits opening. Mentioned cavity is made adjacent to mentioned opening.

EFFECT: efficient elimination of microorganisms at surface of product without usage of too high warmth.

14 cl, 6 dwg

FIELD: animal science.

SUBSTANCE: the present innovation deals with sanitary-hygienic preparation of exercising area, equipment and animals before sampling the sperm in breeding animals. One should clean the floor in exercising area with catholyte at pH being not less than 11.0 and redox potential - not less than -600 mV; air and floor in exercising area, special equipment for animals as service ramps, artificial vaginas and sperm-collecting reservoirs should be disinfected with anolyte at pH being not more than 2.5, redox potential - not less than 1100 mV and active chlorine content of not less than 0.03%; one should wash animals skin, scrotum and prepuce with anolyte at pH being 7.0±0.5 and redox potential of not less than 900 mV. Moreover, one should treat the air in exercising area with anolytic aerosol at liquid drops diameter being not more than 50 mcm at exposure of not less than 30 min, as for artificial vaginas and sperm-collecting reservoirs they should be kept in anolyte for 30-60 min. The innovation provides to obtain high-quality sperm in farm animals.

EFFECT: higher quality of disinfection.

1 ex

FIELD: medical engineering; food industry.

SUBSTANCE: method involves creating ring-shaped continuous cross-section flow of liquid under disinfection and treating it with electromagnetic radiation. Narrow continuous radiation beam is created. The flow is treated by circular scanning with the created radiation beam directed at an angle to the flow with multiple laser radiation refraction in the flow. The device has chamber for producing liquid flow having inlet and outlet tubes, electromagnetic radiation source connected to control unit, acting upon the under disinfection. The device also has rotating mirror having drive connected to the control unit. The chamber has two coaxial cylinders with space left for the liquid to pass. Ring-shaped window is available for letting electromagnetic radiation pass. Mirror member and chamber cylinders axes are superposed. The electromagnetic radiation source has continuous laser radiator optically coupled with via rotating mirror member and internal cylinder window with lateral chamber walls facing each other. One of embodiments involves creating the flow under disinfection having hollow cylinder cross-section, electromagnetic radiation as narrow continuous laser radiation beam transformable into funnel-shaped light flux. Electromagnetic radiation acts upon the produced flux by superposing optical axis of the luminous flux and geometrical axis of the liquid flow under disinfection. The device has also has mirror cone. The chamber for producing liquid flow is fabricated from two coaxial cylinders space formed for letting liquid pass. The internal chamber cylinder has window for electromagnetic radiation to pass through. The mirror cone is mounted on coaxially arranged cylinders. The electromagnetic radiation source has in series mounted laser oscillator and collimator optically coupled via the mirror cone and internal cylinder window to chamber walls facing each other.

EFFECT: high reliability and safety in operation; simplified design.

11 cl, 3 dwg

FIELD: disinfecting of products.

SUBSTANCE: disinfecting and/or warming device has vapor unit for eliminating microorganisms at surface of solid product, in particular, solid food product. Vapor unit has at least one passage for vapor and opening being adjacent to cavity where water vapor jet is applied under pressure through passage for vapor. Water vapor released from opening, is driven into oscillation at frequency, preferably sonic frequency, determined by cavity. Vapor unit has external part, internal wall of which par defines external wall to let vapor in, and internal part, which forms external wall of passage for vapor and limits opening. Mentioned cavity is made adjacent to mentioned opening.

EFFECT: efficient elimination of microorganisms at surface of product without usage of too high warmth.

14 cl, 6 dwg

FIELD: space medicine.

SUBSTANCE: method comprises sampling the agent accumulated by filters of the ventilation system and manual vacuum cleaners, sending the samples to the ground, and setting the specimens on a feeding agent.

EFFECT: enhanced reliability.

FIELD: medicine, other industrial branches.

SUBSTANCE: the present innovation could be applied in case of epidemics and for treating clothes made of fabric, tricot and nonwoven materials of wide assortment. The suggested innovation deals with disinfecting clothes with liquid. Moreover, as liquid it is important to apply water which should be pre-treated with the impact of amplitude-modulating electromagnetic field at its intensity ranged 0.003 to 5 A/m and carrying frequency ranged 0.001-10 MHz, modulating frequency ranged 1-300 Hz and depth of modulation ranged 10-90% for 20 sec, not less. The innovation increases economy, excludes clothes damage and keeps bactericidal properties of clothes treated due to the above-mentioned technique for prolonged period of time.

EFFECT: higher efficiency of disinfection.

1 dwg, 1 tbl

FIELD: medicine, other industrial branches.

SUBSTANCE: the present innovation could be applied in case of epidemics and for treating clothes made of fabric, tricot and nonwoven materials of wide assortment. The suggested innovation deals with disinfecting clothes with liquid. Moreover, as liquid it is important to apply water which should be pre-treated with the impact of electromagnetic field at its intensity ranged 0.003 to 5 A/m and frequency ranged 1-300 Hz for 20 sec, not less. The innovation increases economy, excludes clothes damage and keeps bactericidal properties of clothes treated due to the above-mentioned technique for prolonged period of time.

EFFECT: higher efficiency of disinfection.

1 dwg, 1 tbl

FIELD: medical equipment.

SUBSTANCE: device include bath with disinfection solution, in which flexible endoscope is submerged, the working part being immersed into disinfection solution, as well as disinfection solution feed system for washing tool channel of flexible endoscope inner cavity. The disinfection solution feed system has detachable socket, which is put on distal end of flexible endoscope, its outlet tube is fastened on pump suction inlet, and pump discharge outlet leads through a filter to nozzles, fixed on the bath side walls. Coil spring, freely disposed all along inside the tool channel, is joined by its distal end to piezoelectric cell, which is electrically connected to generator.

EFFECT: increase in quality of flexible endoscopes cleaning and disinfection.

5 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: material which is used in the form of a detail, executed by formation by moulding is described, and it represents the biocompatible binding, containing one or several bonds providing addition of calcium or phosphorus, differing that it is exposed to operations of superficial clearing intended for deducing on a surface. This material is preferably used for manufacturing of ventplants or osteal prostheses.

EFFECT: providion of availability on a surface added to binding calcium and phosphorus.

20 cl, 1 ex

FIELD: technological processes; water treatment.

SUBSTANCE: invention may be used for thermal sterilisation of fluid mediums, and also for heating of return or fresh water in systems of water heating or hot water supply, for drying or thermal treatment of loose materials. Method for treatment of fluid mediums consists in supply of portion or flow of fluid medium into induction heater, and heating of this medium at the background of action of alternating-sign electromagnet field of induction winding of mentioned heater with simultaneous superposition of mechanical vibrations of heating element, at that frequency of mechanical vibrations of heating element corresponds to the frequency of induction winding electromagnet field vibrations. Induction heater is also suggested for treatment of fluid mediums that contains closed magnetic conductor, induction winding, which embraces selected rod of magnetic conductor and is equipped with facility for connection to the source of alternating current, and also tank, in the cavity of which short-circuited electroconductive heating element is installed with the possibility of mechanical vibration under action of alternating-sign electromagnet field of induction winding.

EFFECT: prevention of accumulation of deposits on heat transfer surfaces and provision of efficient sterilisation of water with preservation of high efficiency and low working temperatures.

22 cl, 16 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns medical equipment and is intended for transportation of sterilizer cases with a set of medical instruments. The transport container includes the case, a cover with the latch adaptation, a tool holder and a sealing element from an elastic heat-resistant material. The holder is executed in the form of an elastic tablet with cells of an edge profile with the elastic lamellar clip containing a cone support, the bactericidal filters pressed by linings. The steriliser case is placed in the case of the container representing a box-shaped tight design, having compaction on an internal face open part, and also a demountable cover with rotary blocking latches. In the container case the place for placing of the device in the form of capacity with steam formalin, providing additional sterilisation is provided at closing of the case of the container. In the steriliser case the pallets which height is multiple to height of the case of the steriliser case, are in addition placed. The container case is supplied by handles. The steriliser case design is revealed.

EFFECT: maintenance of sterility and integrity of transported products.

9 cl, 3 dwg

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