Stabilised pharmaceutical submicron suspensions and methods for preparing them
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to a pharmaceutical submicron suspension and to a method for preparing the submicron suspension and is applicable for ophthalmic (local or intravitreal) and nasal application. The ophthalmic aqueous pharmaceutical submicron suspension contains a hydrophobic therapeutic agent prepared in the form of submicron particles with the hydrophobic therapeutic agent presenting nepafenac; where a low-molecular charged polymer contains one or more cellulose polymers which jointly or individually have a molecular weight of less than 200000 kilodalton, and wherein the low-molecular charged polymer has an average degree of polymerisation (DP) making approximately min. 100 and up to approximately 4000; and one or more additives. The low-molecular charged polymer inhibits submicron particle aggregation in the suspension; the submicron particles have an average hydrodynamic radius making less than 1 mcm, and the low-molecular charged polymer represents carboxymethyl cellulose.
EFFECT: using the group of inventions enables preparing the high-active therapeutic agent for ophthalmic application.
16 cl, 5 tbl, 1 ex
Cross-reference to related applications
This application claims the priority under article 35 U.S.C. (US Patent law) §119 of provisional patent application U.S. No. 61/098280, filed September 19, 2008, the contents of which are incorporated here by reference in full.
The technical field to which the invention relates
The present invention relates to pharmaceutical submicron the suspensions, which are used for stabilization of low molecular weight polymers. More specifically, the present invention relates to pharmaceutical submicron the suspensions, which use low molecular weight charged polymer to stabilize therapeutic agent, therapeutic agent is obtained in the form of submicron particles and/or therapeutic agent is in the form of submicron particles in the submicron suspension.
The level of technology
For many years the pharmaceutical industry was developed compositions that include a therapeutic agent, as well as systems and/or media suitable for delivery of therapeutic agents. In the field of ophthalmic preparations, preparations for the ears and nasal preparations considerable efforts have been made to develop a liquid pharmaceutical compositions, in particular in the-breaking solutions, which include system and/or media suitable for delivery of therapeutic agents to the eye, ear or nose. The implementation of such developments, you can encounter various problems and difficulties.
As an example, many therapeutic agents, which exhibit the desired therapeutic properties, can also detect one or more properties, which lead to difficulties in the development of pharmaceutical carriers for delivery of these funds. For example, a therapeutic agent can exhibit a relatively high degree of hydrophobicity and they make such suspension, which can oposredovanie data means unwanted aggregation in aqueous solution. In turn, the final slurry may lose homogeneity and, therefore, may change the quantity delivered to target a therapeutic agent.
Trying to compensate for unwanted data properties to pharmaceutical carriers add many substances, such as surfactants, with the aim of developing new stabilization systems. However, recent data show that many of these new systems can lose biocompatibility and can cause irritation or other adverse effects in human tissues.
In the case of other approaches to compens is its undesirable properties of therapeutic agents, eye, ear and nasal pharmaceutical compositions developed in the form of suspensions. Suspension can be particularly effective when used for placement of therapeutic agents that exhibit properties such as hydrophobicity, resulting insolubility in water or the like. However, a therapeutic agent that is delivered in the form of suspensions, can also exhibit relatively low therapeutic activity when they reach the target tissue of the person.
One of the ways to increase the activity of a therapeutic agent is to increase the surface area of the tool. For example, it has been found that providing a therapeutic agent in the form of submicron particles or nanoparticles may allow to increase the surface area of therapeutic agent and can significantly increase the activity compared with the same therapeutic tool when it is provided in the form of larger particles. It was also shown that such submicron particles may exhibit increased activity when the delivery is made in the composition of submicron suspensions. However, the formation of submicron suspensions can be complicated. For example, there may be difficulties when searching for relevant substances (e.g., grinding), which will clothe part of the formation of submicron particles, since it is necessary that such substances possessed one or more desired properties (for example, the ability to wetting and/or low foaming) in the formation of submicron particles, and eventually will also need to have one or more additional desired properties (such as stability and/or biocompatibility), when they eventually become part of the submicron suspension.
In connection with the foregoing, it would be desirable to receive pharmaceutical submicron suspension (in particular, submicron ophthalmic suspension), the way the suspension and/or substance suitable for the suspension, which allow to overcome the above mentioned problems and disadvantages.
Brief description of the invention
Thus, the present invention is associated with submicron suspension and method of obtaining submicron suspension. According to the method are a therapeutic tool. Therapeutic agent has an initial average hydrodynamic radius that is at least about 900 nanometers, more usually at least about 1.0 micron, and even more usually at least about 1.3 microns and even possibly at least 2.0 μm, 4.0 μm or more. Therapeutic agent obyedinenie is camping with a polymeric material to obtain a mixture. The polymeric material includes a low molecular weight charged polymer and may be composed entirely or substantially entirely of a low molecular weight charged polymer. The mixture is then processed to convert the particles of therapeutic agent in smaller submicron particles of a therapeutic agent, where submicron particles of a therapeutic agent have an average hydrodynamic radius, which is less than 1 micron, more usually not more than 850 nanometers, still more usually not more than 700 nm. According to this mixture becomes a submicron suspension preferably adding one or more excipients to the mixture and/or during subsequent processing. Mainly low molecular weight charged polymer inhibits aggregation of particles and submicron particles during processing and/or receiving pharmaceutical submicron nanosuspension.
In preferred embodiments therapeutic agent is an inhibitor of receptor tyrosine kinase (IRTK) or nonsteroidal anti-inflammatory drug (NSAID) (eg, nepafenac). Also, in preferred embodiments, low molecular weight charged polymer is an essentially fully or completely carboxymethylcellulose.p> Detailed description of the invention
The present invention is based on obtaining pharmaceutical compositions and, in particular, submicron suspension, which includes a therapeutic tool in the form of submicron particles and includes a polymeric material (e.g., a charged polymer), which is involved in the stabilization of therapeutic agent in the submicron suspension. The polymeric material can also be used to stabilize therapeutic agent, when relatively large particles of a therapeutic agent is reduced to submicron or even nanoparticles with one or more devices for processing. It is assumed that the pharmaceutical submicron suspension can be used in various pharmaceutical situations, but can be particularly useful for ophthalmic and nasal applications. Thus, it is assumed that the submicron suspension can be applied topically in the ear or the nose of a mammal, in particular humans. Most preferably, however, the submicron suspension is an ophthalmic suspension, which can be applied topically or intravitreal in the human eye.
Used herein, the term "stabilize" and its conjugations, as well as the terms used in relation to a polymeric material, a stabilizing t is rapeutique means, at least means that the polymeric material inhibits aggregation of particles of therapeutic agent. Used herein, the term "submicron", as used in respect of the particles means that the particles have a size that is less than one micron, however, such particles may have a size which is not more than 850 nanometers, and perhaps not more than 700 nm. Submicron suspension is a suspension containing such particles suspended in the solution. Used herein, the term "nanoparticle" means a particle having a size that equals no more than 200 nanometers, however, such particles may have a size that is not less than 70 nanometers, or maybe even no more than 50 nanometers. Nanosuspension is a suspension containing such nanoparticles suspended in solution, and submicron suspension of the present invention may be nanosuspension, if the suspended particles are sufficiently small.
Unless otherwise specified, the particle size is determined using the device to determine the size. Several measuring devices are commercially available for the measurement of particle size with very little measurement error. These devices determine the particle size with the aid of the people, for example, a method of dynamic light scattering and then calculate the average hydrodynamic radius of the particle group of particles. The average values of the radii of the particles are, unless otherwise specified, are discussing here the size of the particles. Preferred typical device is ZETASIZER NANO, which is commercially available from Malvern Instruments Ltd., Enigma Business Park, Grovewood Road, Worcestershire WR14 1XZ, United Kingdom.
The measuring device for measuring the particle size may require that prior to measurement of particle size in suspensions or other solutions have been provided with specific settings for the device. If required, the parameters can be as follows: viscosity at zero shear rate (η0) solution, which can be defined using oscillometry-viscometer; the refractive index of the particles (PMh) can be determined using the method of monitoring line Becke in the microscope; the refractive index of any diluent (PMp) can be determined with a Refractometer; and the dielectric constant (κ) can be determined by determining the capacity. As a rule, to determine the size of particles it is preferable to use solutions with relatively high concentrations of particles, before the multiple scattering and the interaction of particles changes the Yat result.
Unless otherwise indicated, percentages are provided for the components of the pharmaceutical compositions of the present invention, represent the ratio of mass/volume percent (wt./vol.).
Typically submicron suspension of the present invention includes a therapeutic tool. A therapeutic agent may be the sole therapeutic agent or it may consist of several therapeutic agents. Therapeutic remedies include as non-limiting examples, any component, compound or small molecule that can be used to produce the desired therapeutic effect. For example, the desired effect may include treatment, mitigation, treatment or prevention of a disease or condition. A therapeutic agent may also have an impact on the structure and function of body parts or organs of the subject.
Generally, it is preferable that a therapeutic tool include at least one hydrophobic drug or therapeutic agent. Hydrophobic therapeutic agent includes a tool that is poorly soluble in aqueous medium (for example, not completely dissolved in the medium at a concentration at which it is introduced into the aqueous composition, in particular, when the POG is ujena in this aquatic environment without auxiliary means, to facilitate solubilization of the tool. Therapeutic agent is typically at least about 0,001, more usually at least about 0.01 and further characterized by at least about 0.1 wt./vol.% in submicron suspension. Therapeutic agent is typically less than about 10, more usually less than about 5 and further characterized by less than about 2.0 wt./vol.% in submicron suspension.
A therapeutic agent of the present invention is, preferably, a solid substance in the form of particles. However, it is also assumed that a therapeutic tool, such as a therapeutic agent in liquid form, can be adsorbed or otherwise placed on the particles (for example, polymer particles) for use in the present invention.
A preferred class of therapeutic agents includes eye, ear and nasal drug substances, in particular hydrophobic and/or low eye, ear and nasal drug. Non-limiting examples include anti-glaucoma, antiangiogenic tools, anti-infective tools, anti-inflammatory agents, growth factors, immunosuppressants and anti-allergic drugs. Anti-glaucoma include beta-blockers, such as betaxolol levobetaxolol, inhibitors of carbonic anhydrase, such as brinzolamide and dorzolamide, prostaglandins, such as travoprost, bimatoprost and latanoprost (serotonergic tools, muscarinic funds, the dopamine agonists. Antiangiogenic tools include anecortave acetate (RETAANE™, Alcon™ Laboratories, Inc. of Fort Worth, Tex.) and inhibitors of the receptor tyrosine kinase. Anti-inflammatory agents include non-steroidal and steroidal anti-inflammatory drugs such as triamcinolone actinide, suprofen, diclofenac, Ketorolac, nepafenac, rimexolone and tetrahydrocortisol. The growth factors include EGF (epidermal growth factor) or VEGF (factor vascular endothelial growth). Anti-allergic drugs include olopatadine, epinastine. Ophthalmological medicinal substance can be represented in the form of pharmaceutically acceptable salts.
It was found that the submicron suspension of the present invention is particularly suitable for ophthalmic applications (e.g., local or intravitreal), when a therapeutic tool which is essentially a fully or a fully inhibitor of receptor tyrosine kinase (IRTK). Thus, in one preferred embodiment, therapeutic agent can represent at least 50%, more than is characteristic is at least 80% and even more usually at least 95% (e.g., 100%) by weight of IRTC.
Preferred IRTC for use in the present invention is a multipurpose inhibitor of receptor tyrosine kinase. Most preferred are IRD profile of binding to multiple targets (multi-profile binding), such as N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-were)urea, having the profile link, substantially similar to the profile shown in Table 1 below. Additional multipurpose inhibitors of the receptor tyrosine kinase, proposed for use in the compositions of the present invention, are described in the application U.S. number 2004/0235892 included here by reference in full. Used herein, the term "multipurpose inhibitor of receptor tyrosine kinase" refers to compounds having a profile of binding to receptors, characterized by the selectivity in respect of a number of receptors, which, as shown, are important in angiogenesis, such as the profile shown in Table 1, and described in co-pending application, U.S. number 2006/0189608 included here by reference in full. More specifically, the preferred profile of the binding of the compounds of the multipurpose inhibitors of the receptor tyrosine kinase for use in the compositions of the present invention is one which by KDR (receptor intracellular domain, containing the kinase insert, VEGFR2), Tie-2 and DERIVED (the receptor for platelet-derived growth factor).
|The selectivity profile against kinases for RTK inhibitor|
All data are presented as values IC50for kinase inhibitor in testing with the help of an enzyme in a cell-free system. Values were determined at 1 mm ATP.
Another highly preferred therapeutic agent suitable for use in the suspensions of the present invention, is as a non-limiting note the RA non-steroidal anti-inflammatory agent. Preferred non-steroidal anti-inflammatory drugs are inhibitors of the synthesis of prostaglandin H (COX-1 or COX-2), also known as inhibitors of cyclooxygenase type 1 and type 2, such as diclofenac, flurbiprofen, Ketorolac, suprofen, nepafenac, amfenac, indomethacin, naproxen, ibuprofen, bromfenac, Ketoprofen, meclofenamate, piroxicam, sulindac, mefenamovaya acid, diflunisal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumeton, etodolac, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456, tenoxicam and carprofen; selective inhibitors of cyclooxygenase type 2, such as NS-398, viox, celecoxib, P54, etodolac, L-804600 and S-33516; antagonists PHAT (platelet activating factor, PAF), such as SR-27417, A-137491, ABT-299, epatant, epatant, menuparent E-6123, BN-50727, noparent and mdiparent; inhibitors of PDE IV (PDE), such as ariflo, terbutalin, rolipram, filaminast, piclamilast, cipamfylline, CG-1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636, BAY-19-8004 and roflumilast; inhibitors of cytokine production, such as inhibitors of the transcription factor NFkB; or other anti-inflammatory agents known to the person skilled in the art. Preferred compounds for use as inhibitors of prostaglandin synthesis in the compositions and methods of the present invention are phenylacetamide selected the s of 2-amino-3-(4-perbenzoic)phenylacetamide, 2-amino-3-benzoylferrocene (nepafenac) and 2-amino-3-(4-chlorbenzoyl)phenylacetamide, most preferred of which is nepafenac.
The concentration of anti-inflammatory drugs contained in the compositions of the present invention, will vary depending on the selected vehicle or vehicles and the type subjected to the treatment of inflammation. Concentration will be sufficient to reduce inflammation in target tissues of the eye, ear or nose after topical application of compositions for these tissues. This number is referred to here as "effective against inflammation." The compositions of the present invention will usually contain one or more anti-inflammatory drugs in the amount of from about 0.01 to about 3.0 wt./vol.%, more usually from about 0.05 to about 1.0 wt./vol.% and even more significant from about 0.08 to about 0.5 wt./vol.%.
Assume that a is preferred that therapeutic agent (for example, IRD or NSAIDs, such as nepafenac), suspended in the suspension of the present invention, was hydrophobic. In this regard, therapeutic agent typically has a value of log D more than 0.1, more preferably more than 0.4, more preferably more than 0.6 and even, perhaps, more than 1.0 or even more than 1.5.
As used here, log D is assigned the e total concentration of all forms of therapeutic agents (ionized plus UN-ionized) in each of the two phases - in octanone phase and aqueous phase. To determine the distribution coefficient establish the pH of the aqueous phase is equal to 7.4, so that the pH value with the introduction of compounds was not significantly changed. The logarithm of the ratio total concentration of various forms of the solute in the same solvent to the total concentration of its forms in another solvent call Log D:
Log DOct./water= log([Rast. in]the octanol/([Rast. in]ion. water+ [Rast. in]neutron. water)).
Other tools that may be useful in suspensions and methods of the invention include anti-VEGF antibody (endothelial growth factor vascular) (e.g., bevacizumab or ranibizumab), VEGF trap molecules siRNA (small interfering RNA) or a mixture thereof, directed at least two tyrosinekinase receptor with values IC50less than 200 nm in Table 1; glucocorticoids (e.g. dexamethasone, formation, Madison, betamethasone, triamcinolone, triamcinolone acetonide, prednisone, prednisolone, hydrocortisone, rimexolone and their pharmaceutically acceptable salts, prednicarbate, deflazacort, halometasone, tixocortol, prednisone (21-diethylaminoacetate), prednesol, paramethasone, methylprednisolone, meprednisone, mazipredon, isoflupredone, halopedia acetate, halcinonide, farmacita, flurandrenolide, flupredniden is h, fluprednidene acetate, flaperon acetate, fluocortolone, fluocortin butyl, fluocinonide, fluoqinolona acetonide, flunisolide, flumetazon, fludrocortisone, Flocklined, enoxolone, difluprednate, diflucortolone, diflorasone diacetate, desoximetasone, desonide, destinaton, cortisol, corticosterone, cortisone, cloprednol, clocortolone, clobetasol, clobetasol, chloroprednisone, cafestol, budesonide, beclomethasone, amcinonide, allopregnane acetonide, alclometasone, 21-acetoxyphenyl, taloned, diflorasone acetate, deallocate, EN-26988, budesonide and dellcachedevicelocation); naphthohydroquinone antibiotics (e.g., rifamycin).
The composition of the polymer material of the present invention may include various polymers. Examples of potentially suitable polymers include as non-limiting examples of chondroitin sulfate, low molecular weight hyaluronic acid or other low molecular weight charged polymers, which possess the desired ability to reduce or decrease the surface tension. It is also assumed that the submicron suspension in this application may optionally include or not to include polymers comprising a polymeric material. Examples of potentially suitable additional polymers include, as non-limiting approx the ditch polyols, polymers based on NIPAM (N-isopropylacrylamide), polyethylene, combinations thereof or the like.
Typically, however, the polymeric material will contain one or more low molecular weight polymers, which are preferably charged. Used herein, the expression "low molecular weight"is used to describe polymers in the polymeric material, means that these polymers in the polymeric material together have an average molecular weight of less than 500000, more usually less than 200,000, and even more typical less than 100,000 kilodaltons (kDa). The viscosity of 1% solution of the polymer material in the treated water is usually at least a 3.0, more usually at least 4,5 and further characterized by at least 6.0 centipoise at 25°C., and the viscosity of this solution, usually less than about 100, more usually less than about 20 and even more usually less than about 8.0 centipoise at 25°C.
The polymers of cellulose, such as karboksimetilcelljulozy (CMC, CMC) polymers are particularly preferred polymeric material submicron suspension. Used herein, "polymer cellulose" includes any polymer that has two or more groups corresponding to the formula (C6H10O5). Such polymers can be charged when they are in salt form. Especially predpochtitel the governmental cellulose polymers are the salt of the polymer of carboxymethylcellulose, such as sodium carboxymethylcellulose. Sodium carboxymethylcellulose, suitable for use in the present invention has a degree of substitution (Sz) at least 0.2 and preferably at least about 0.5. The degree of substitution of sodium carboxymethylcellulose may be up to about 2.5, preferably up to about 0.9. The degree of polymerization (SP) sodium carboxymethyl cellulose is at least about 100, preferably at least about 200. The degree of polymerization of sodium carboxymethylcellulose may be up to about 4000, preferably up to about 1000. One illustrative example of a suitable polymer cellulose is sodium carboxymethyl cellulose sold under the trademark AQUALON 7L2P and CMC 7LF, which is commercially available from Hercules Inc.
It was found that the submicron suspension of the present invention is particularly suitable for ophthalmic applications (e.g., local or intravitreal), when a polymeric material which includes essentially completely or are completely polymer cellulose (for example, salt of the polymer of cellulose, such as sodium carboxymethylcellulose). Thus, the polymeric material may constitute at least 50%, more usually at least 80% and even more usually at least 9% (for example, 100%) by weight of the polymer cellulose (for example, salt of the polymer of cellulose, such as sodium carboxymethylcellulose).
In submicron suspension of the present invention can be incorporated in various additional components. Submicron suspension of the present invention are typically water and, as a rule, contain a significant amount (e.g., at least 80 or 90 wt./vol.%) water. Add other additional components will usually depend on how the submicron suspension should be entered.
If submicron suspension is applied topically to the eye or other tissue of a human, then the suspension can, as a rule, contain various additional components. Such components include, as non-limiting examples of additional therapeutic agents, antimicrobial agents, agents to obtain suspensions, surfactants, substances that regulate toychest, buffering agents, antioxidants, changing the viscosity tools, combinations thereof or the like.
If submicron suspension should be injected into the body, in particular intravitreal, by injection (e.g., with a needle) or otherwise, then it is usually desirable to minimize the amount of Ni is sustained fashion components, included in the submicron suspension. In this example may be the case when the submicron suspension comprises or essentially consists of the following components: a polymer, a therapeutic agent and water.
Submicron suspension can be obtained in various ways within the scope of the present invention. In accordance with the preferred method of submicron suspension get by applying the following stages: (i) a therapeutic tool in the form of particles mixed with a polymeric material and possible excipients to obtain a mixture; (ii) the mixture is sent to the device (e.g., a grinder), which is designed to reduce the size of the particles of therapeutic agent; and (iii) the mixture is combined with water and possible excipients to obtain a submicron suspension.
The quantity of polymeric material and a therapeutic agent in the mixture can vary and may depend on the processing that will be applied to the mixture. In General, however, it is preferable that the mixture was water, so that a polymeric material and a therapeutic agent are added to water. In the preferred embodiments, and particularly in embodiments where is included a significant proportion of IRD as a therapeutic environments is tion and a significant portion of the polymer is cellulose, the mass ratio between therapeutic agent and a polymeric material typically is in the range from about 10:1 to about 1:10, more usually from about 5:1 to about 1:4 and even more usually from about 1.5:1 to about 1:1. In such embodiments, the mixture will typically contain at least about 0.5, more usually at least about 1.5, and even more usually at least about 3.0 wt./vol.% and will typically contain less than about 12, more usually less than about 8, and even more usually less than about 4.0 wt./vol.% a therapeutic agent. In addition, in such embodiments, the mixture will typically contain at least about 0.5, more usually at least about 1.2, and even more usually at least about 2.5 wt./vol.% and will typically contain less than about 12, more usually less than about 7, and even more usually less than about 3.8 wt./vol.% polymer material.
Examples of devices for reducing the size of particles include as non-limiting examples of devices that perform homogenization under high pressure and/or mixing with a large shear force. The preferred device for reducing the particle size of therapeutic agent is a device for wet grinding. Such a device may include a chamber filled with pulverised grains, which usually have a size of from about 0.05 mm to about 1 mm (e.g., 0.2 mm) in diameter. The camera then can rotate at a speed which is typically from about 2,000 to about 4,000 revolutions per minute (rpm). One illustrative wet grinder is MINICER High Grinding System, commercially available from Netzsche Fine Particle Technology, Exton, PA, USA. It should be understood that there may be a need to ensure that the particles were treated in the device (e.g., grinding) a few times before you will reach the desired sub-micron or nano-sized particles.
The particles of therapeutic agent before processing device or processing typically have an average particle size greater than 500 nm, more usually more than 1.0 micron, and even more typical of more than about 1.3 microns. After processing device or processing of particles otherwise particles either become submicron particles, or become less sub-micron particles with a particle size that is less than about 900 nm, more usually less than about 820 nanometers and even more usually less than about 730 nanometers. In some embodiments (for example, in the case of a therapeutic agent of IRTC) may be desirable that the particle size of therapeutic agent after processing device b is l larger than a certain size (for example, the size of nanoparticles) to provide a therapeutic effect over an extended period of time for funds. Thus, submicron particles can have a size greater than about 200 nanometers, more typical of more than about 350 nanometers and even, perhaps, more than about 400 nanometers. In still other embodiments where it is desirable to provide a greater therapeutic effect within a shorter period of time, it may be desirable to have a therapeutic tool was even less after processing in the device. In such embodiments submicron particles can have a particle size that is less than about 200 nanometers, more usually less than about 150 nanometers, and even more possibly less than about 100 nanometers.
For other therapeutic agents, including NSAIDs, such as nepafenac, the average particle size may be different. This amount is generally at least about 50 nanometers, more usually at least about 200 nanometers, and even more usually at least about 250 nanometers. This particle size is generally less than 820 nm, more usually less than 500 nanometers, and even more usually less than 350 nanometers.
At some point before, during or after the treatment, therapeutic means to achieve smaller RA is a measure of the particles can be added excipients and/or active substances for therapeutic tool, polymeric material, and mixtures or combinations thereof to obtain a submicron suspension. Thus, it is assumed that the auxiliary substances or additional active ingredients may be added before or after the unification of the polymer material with a therapeutic agent, before or after the particle size will be reduced or at any time during processing. In a preferred step, the mixture is optionally diluted, preferably purified water, after reaching the desired particle size, so it submicron composition with finite mass./about. the percentage of polymeric material and a therapeutic agent. Upon completion of the submicron suspension will generally contain at least about 0.1, more usually at least about 0.5, and even more usually at least about 1.0 wt./vol.% and will typically contain less than about 7, more usually less than about 5, and even more usually less than about 2.5 wt./vol.% a therapeutic agent. Also submicron suspension will generally contain at least about 0.1, more usually at least about 0.5, and even more usually at least about 1.0 wt./vol.% and will typically contain less than about 7, more usually less than about 5, and even more usually less than about 2.5 wt./the B.% polymer material.
Predominantly polymeric material of the present invention facilitates the processing (for example, processing device, such as grinding) of therapeutic agent in submicron particles and simultaneously contributes to the inhibition of aggregation of particles of a therapeutic agent and/or has a tendency to detect the relatively low degree of foaming during such processing. In addition, the polymer material can inhibit the aggregation of submicron particles in the submicron suspension. Not limited to the assumption, suppose that the charge of low molecular weight charged polymer promotes close ties between the polymer and therapeutic agent, which usually has the opposite charge. In turn, this binding helps prevent aggregation of therapeutic tools. As additional advantages of the polymeric material of the present invention tends to be biocompatible.
The applicants have included all references cited in full in this description. In addition, in the case when the quantity, concentration, or other value or parameter is specified as either a range, preferred range or enumeration of upper preferable values and lower preferable values, this should be understood as the specific rscr the ment of all ranges, obtained from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether you are specifying ranges separately. When this is the range of numerical values, unless otherwise specified, the range includes extreme values and all integer and fractional values within the range. It is not intended that the scope of the invention limited to the specific values listed in the definition range.
Other embodiments of the present invention will be obvious to specialists in this area when considering the present description and the practical implementation of the present invention disclosed here. This suggests that the present description and examples be considered only as an illustration, with the true scope and essence of the invention defined in the following claims and its equivalents.
Experiments and comparison Examples
To determine the effect on the aggregation of particles received submicron suspension, which contains IRTC and carboxymethylcellulose (CMC), in accordance with the idea of the present invention. In particular, a mixture of water, CMC and IRTC crushed using MicroCer Netzch High Energy Grinding System. Then add a further quantity of water to the mixture to obtain su the micron suspension in the form of a solution with a viscosity of 4 CP. The particle size of submicron suspensions was determined directly after receipt of the suspension. After that submicron suspension was frozen and then the particle size was again determined after one week, six weeks and eight weeks after receipt of the suspension. Each of these measurements was performed using the instrument for measuring particle size ZETASIZER NANO, commercially available from Malvern Instruments. The results in Table A together with the coefficient of polydispersity (Kpfollowing:
|The retention time||Particle size|
As what you can see significant changes in the size of the particles does not occur. This indicates that the aggregation of particles in each interval of time hardly ever or never happens. In particular, the device for determining particle size results in larger particles, when the particles aggregate. As an indicator of particle size in Table A is not essentially changed, significant aggregation of particles in the submicron suspension at specified intervals of time does not occur. It should be noted that in the Table And the size of the particles may not be accurate, depending on the accuracy of the data input into the device for determining particle size, however, changing to a small extent sizes nevertheless fully reflects the low level of aggregation, because the data input to the device for determining particle size was correlated with subsequent measurements of the same solution.
We also carried out experiments for a number of different possible additives for grinding and compared with CMC.
|Additive for grinding, %||The level of foaming||The homogeneity of the submicron suspension|
|Sodium CMC, 0,8-2,0%||Very low||High homogeneity|
|Polysorbate (PS) 80, 0,2%||Average||High homogeneity|
|Poly(styrelseledamot) (PSSC), 4%||Low||Inhomogeneous, non-wetted|
|PSC 3,5%/PS 80, 0,2%||Average||High homogeneity|
|Hyaluronic acid, sodium salt, 0,7%||High||Inhomogeneous|
As you can see, CMC minimizes foaming and provides the desired level of wetting.
For additional study on aggregation of particles were grinding of nepafenac and carboxymethylcellulose (CMC) using High Energy Grinding System. Then add the other components to obtain ophthalmic suspension in the Table:
|Sodium carboxymethyl lulose 7LF||0,06|
|The carbopol 974P||0,5|
|NAOH/HCl||pH to 7.4|
|Purified water||Brought to 100%|
Controlled changes submicron suspension for 13 weeks at 25 and 40°C. the particle Size was estimated using the method of dynamic light scattering (Zatasizer) and presented below. Up to 13 weeks of the particle size was not significantly changed in both temperature values.
|Storage conditions||The average particle size|
|4 weeks||25 what C||643|
1. Ophthalmic aqueous pharmaceutical submicron suspension containing:
hydrophobic therapeutic agent, which is obtained in the form of submicron particles, where therapeutic agent has a log D more than 0.1, and a hydrophobic therapeutic agent is nepafenac;
low molecular weight charged polymer, where the low molecular weight polymer comprises one or more cellulose polymers, alone or together have an average molecular weight of less than 200,000 in kilodaltons (kDa) and low molecular weight charged polymer has an average degree of polymerization (SP), which is at least about 100 up to about 4000; and
one or more auxiliary substances, where
i) low molecular weight charged polymer inhibits the aggregation of submicron particles in suspension; and
ii) submicron particles have an average hydrodynamic radius, which is less than 1 micron, where low molecular weight charged polymer is a carboxymethyl cellulose.
2. The suspension according to claim 1, where one or several who are excipients include water.
3. The suspension according to claim 1, where therapeutic agent is more than 0.6 log D.
4. The suspension according to claim 1, where the viscosity of 1% solution of low molecular weight charged polymer in purified water is at least 4.2 centipoise at 25°C and the viscosity of this solution is less than about 20 centipoise at 25°C.
5. The suspension according to claim 1, where therapeutic agent has a log D more than 1.0.
6. The suspension according to claim 5, where the average degree of polymerization is at least about 200.
7. The suspension according to claim 5, where the average degree of polymerization up to about 1000.
8. The suspension according to claim 1, where the suspension is an ophthalmic suspension suitable for application to the human eye.
9. The suspension of claim 8, where the suspension obtained for intravitreal injection.
10. The method of obtaining ophthalmic aqueous pharmaceutical submicron suspensions, where the method includes:
providing a hydrophobic therapeutic agent in the form of particles, where the particles have an average hydrodynamic radius of at least 1 micron and where therapeutic agent is more than 0.1 log D;
combining particles of a therapeutic agent with a low molecular weight charged polymer to obtain a mixture, where low molecular weight charged polymer comprises one or more polymers of cellulose, which is mi on its own or together have an average molecular weight which is less than 200000 kilodaltons (kDa);
processing the mixture to convert the particles of therapeutic agent in submicron particles of a therapeutic agent, where submicron particles of a therapeutic agent have an average hydrodynamic radius of less than 900 nm, where the step of processing the mixture comprises wet grinding the mixture; and
combining the mixture with one or more excipients with obtaining, thus, pharmaceutical submicron suspensions, where low molecular weight charged polymer inhibits aggregation of particles and submicron particles during processing or upon receipt of a suspension, where the hydrophobic therapeutic agent is nepafenac and low molecular weight charged polymer is a carboxymethyl cellulose.
11. The method according to claim 10, where therapeutic agent is more than 0.6 log D.
12. The method according to claim 10, where wet grinding mixture is performed several times.
13. The method according to claim 10, where one or more excipients include water.
14. The method according to claim 10, where therapeutic agent has a log D more than 1.0.
15. The method according to claim 10, where the suspension is an ophthalmic suspension suitable for application to the eye.
16. The method according to claim 10, further comprising the injection of the suspension into the eyes of the man put the m intravitreal injection.
SUBSTANCE: invention relates to ophthalmological pharmaceutical compositions, namely to sorafenib-based compositions, and is intended for treatment of non-cancer neoangiogenic pathologies of the eye. The invention provides application of sorafenib for production of an ophthalmological pharmaceutical composition for local, subconjunctival, subretinal or periocular introduction, for introduction by means of near-scleral injection or for introduction by means of retrobulbar injection. The said composition additionally includes VDA, corticosteroids, angiostatic cortisones, albendazole, mebendazole, carboanhydrase inhibitors (CAI), canabinoids, non-steroid anti-inflammatory drugs (NSAID), selective COX-2 inhibitors, iNOS inhibitors, molecules, interacting with inflammatory mediators, molecules with immunosuppressive action, beta-lactamines (penicillins, cephalosporins), macrolides, tetracyclines, fluoroquinolones, natural polypeptides with antibacterial activity and their fragments, SiRNA.
EFFECT: invention provides an efficient ophthalmological pharmaceutical sorafenib-based composition for treatment of non-cancer neoangiogenic pathologies of the eye.
7 cl, 2 tbl, 3 dwg, 1 ex
SUBSTANCE: group of inventions relates to ophthalmology and is intended for delivery of a therapeutic preparation into an eye. An eye device contains a non-biodegradable mass of material, which includes a hydrophobic component, represented in an amount, sufficient for contact angle of the material to be larger than 50° and formed of at least 80% by weight of acryl material. The device also contains the therapeutic preparation, located on the peripheral surface of the material mass. The therapeutic preparation is hydrophobic and has a coefficient of distribution in the system octane/water PC Log P, equal at least to 1.0. The material mass is formed for introduction into the human eye. Attraction of the therapeutic agent to the hydrophobic part controls a delayed release of the therapeutic preparation in such a way that less than 50 wt % of the therapeutic preparation is released from the eye device into the basic salt solution (BSS) within at least three days. The method of the eye device obtaining includes submergence of the material mass into the solution, which contains a solvent and the therapeutic preparation.
EFFECT: application of the group of inventions ensures delivery of the therapeutic preparation into the eye within long period of time.
19 cl, 12 dwg, 1 tbl, 12 ex
SUBSTANCE: preparation comprises branched polyhexamethylene guanidine in the form of hydrochloride, taurine, a promoting ingredient, additives and water. The promoting ingredient is specified in succinic acid or its pharmaceutically acceptable salt, while the additives are specified in a group consisting of physiologically acceptable alkaline or acidic agents and a salt tonic agent specified in physiologically acceptable sodium or potassium salts or mixtures thereof.
EFFECT: more effective therapeutic effectiveness for pathological conditions of the eyes, and a potential comorbid bacterial infection.
3 cl, 3 tbl, 4 ex
SUBSTANCE: physiotherapeutic goggle device BLEPHASTEAM is placed over an orbital cavity. Restasis is applied on cotton pads in the amount of 4 drops equally spaced over each cotton pad. The pads are placed into the device. The physiotherapeutic exposure covers open eyelids for 10 minutes daily. The therapeutic course consists of 20 sessions.
EFFECT: method provides a pronounced anti-inflammatory, reparative, anti-allergic effect with reducing the length of treatment and ensuring cost advantages of using the expensive drug Restasis evaporated in the goggle BLEPHASTEAM, allowing for the simultaneous effect on the cornea, conjunctiva and eyelids.
8 dwg, 2 ex
SUBSTANCE: treating retinal and/or vitreous hemorrhages is ensured by a session of subcutaneous administration of Histochrom 0.5 ml into a mastoid bone, Echinacea compositum 1.0 ml into a temporal fossa, Gemase 2500-5000 IU parabulbary dissolved in Lymphomyosot 0.5-1.0 ml. The therapeutic course is 10-15 sessions, either daily or every second day.
EFFECT: faster resolution of the intraocular hemorrhages, prevention of retinal injuries by toxic decay products, higher visual acuity.
SUBSTANCE: invention refers to medicine, namely to ophthalmology, to preparations for the treatment and prevention of eye diseases, and may be used in visual impairment, development and progression of eye diseases, as well as for the prevention and maintenance therapy of oxular diseases. Substance of the invention consists in the fact that a therapeutic eye balsam is characterised by the fact that it contains the ingredients in ratio in grams per 100 g of the therapeutic eye balsam of the following formulation: Siberian fir extract - 48.540 g, 5% propolis extract - 10.000 g, 0.9% physiological saline - 38.540 g, neoselen (food supplement) - 0.971 g, vitamin B2 - 0.007 g, citric acid - 0.971 g, ascorbic acid - 0.971 g that promotes achieving the declared technical effect ensured by the given proportions. The presented balsam enables the higher clinical effectiveness in all the forms of ocular pathologies, provides the anti-inflammatory effect on the eye mucosa and cornea, as well as delivers a good result in the post-traumatic and post-operative treatment.
EFFECT: therapeutic eye balsam containing the natural ingredients in certain proportions provides the integrated therapeutic effect on the visual organs and has found use in a great number of grateful patients.
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to a pharmaceutical composition and methods of using it in treating insufficient eye lubrication, related symptoms or adverse conditions related to insufficient eye lubrication. The pharmaceutical composition contains human PRG4, its wetting fragment, a homologue or an isoform suspended in ophthalmologically acceptable balanced saline. The pharmaceutical composition can also contain one or more ophthalmologically acceptable agents specified in a group consisting of a sedative, an excipient, a binding agent, a vasoconstrictor, an emollient, sodium hyaluronate, hyaluronic acid and surface active phospholipids in a pharmaceutically acceptable carrier for topical use.
EFFECT: group of inventions provides treating the diseases related to impaired corneal and conjunctival wetting.
15 cl, 10 dwg, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: what is presented is a method for the suppression of physiological disorders related to abnormal angiogenesis, specified in retinopathy, diabetic retinopathy, macular degeneration, retinopathy of prematurity, age-related macular degeneration, pancreatic tumour and glioma, involving the administration of an effective amount of 3-[(5-(2,3-dimethoxy-6-methyl-1,4-benzoquinolinyl)]-2-nonyl-2-propenoic acid (E3330) or its pharmaceutically acceptable salts or solvates. The decreased EHF-1α, NFKβ, AP-1 activity by E3330 and the suppression thereby of the growth, survival. Migration and metastasis of tumour cells are accompanied by the absence of the major suppression of the growth of normal cells (hemopoietic embyo cells or CD34+ human progenitors). Besides, E3330 has enhanced the therapeutic effect of other cytotoxic preparations.
EFFECT: reducing the amount of VGEF and proliferation of retinal endothelial cells by E333O even in the presence of a fibroblast growth factor, both in the normal oxygen conditions, and in the hypoxia by the inhibition of the oxidation-reduction activity of Apel/Ref-1.
12 cl, 35 dwg
SUBSTANCE: invention refers to medicine, namely to eye drops, and aims at treating dry eye syndrome, as well as bacterial conjunctivitis and/or blepharitis. The preparation comprises a combination of the ingredients, a prolonging ingredient, additives and water. The combination of the active ingredients contains branched polyhexamethylene guanidine and sulphacetamide; the prolonging ingredient is specified in a group consisting of polyvinyl alcohol, water-soluble methyl cellulose or hydroxypropyl methyl cellulose; the additives are specified in a group consisting of a group consisting of physiologically acceptable alkaline or acid agents, and a saline tonic agent.
EFFECT: using the invention enables higher clinical effectiveness of dry eye syndrome, as well as a comorbid bacterial infection, as the preparation possesses the bactericidal effect consistent with the effect of 20% sulphacetamide causing no irritant effect on long use.
4 cl, 3 tbl, 6 ex
SUBSTANCE: invention relates to medicine, namely ophthalmology. The method involves a transepithelial corneal collagen crosslinking. That is preceded with a single bath electrophoresis with 1% riboflavin mononucleotide. That is ensured by an initial current of 0.2 mA to be increased gradually to 1 mA, at a pitch of 0.2 mA for 2 minutes. That is followed by an ultraviolet corneal exposure. The exposure is conducted at wave length 370 nm, power 3 mWt/cm2 and combined with instillation of a riboflavin solution. The solution contains 0.1% riboflavin mononucleotide and 20% dextran.
EFFECT: method provides more effective riboflavin delivery to the corneal stroma for one procedure providing the intraocular protection against ultraviolet light.
2 cl, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry and represents a formulation of a perfluorinated blood substitute emulsion for biomedical applications, containing: perfluorinated hydrocarbons, emulsifying agents and an electrolyte solution differing by the fact that it contains a binary mixture of two perfluorinated hydrocarbons in ratio 1.55 to 1.99 in the concentration of 5 - 1000 g/l, with an average particle size of a perfluororganic compound of 25 - 250 nm; a binary mixture of the emulsifying agents in ratio 1.55 to 1.99 that are non-ionic block copolymers of ethylene oxide and propylene oxide - proxanoles: proxanole-268/proxanole-168; proxanole-268 in the concentration of 1 - 200 g/l with the molecular weight of 7 - 14 thousand Da; proxanole-168 in the concentration of 1 - 200 g/l with the molecular weight of 5 - 7 thousand Da; the electrolyte solution: NaH2PO4 - 0.18-0.25 g/l; NaCl - 5.5-6.5 g/l; and/or KCl - 0.37-0.41 g/l; and/or MgCl2 - 0.17-0.21 g/l; and/or NaHCO3 - 0.35-0.7 g/l; and/or glucose - 1.5-2.5 g/l.
EFFECT: invention ensures formulating the perfluorinated blood substitute with better aggregation and sedimentation stability and lower toxicity.
2 cl, 9 ex
SUBSTANCE: agent contains 0.2% Pyriton, an emulsifier, an emollient - isopropyl myristate, and a solvent. The emulsifier is presented by glycerol cocoate PEG-7; the emollient is presented by triglycerides of caprylic and capric acids; the solvent is water. Besides, the agent additionally contains glycerol, cyclomethicone, urea, allantoin and a flavouring agent. All the ingredients of the agent are taken in certain mass ratio.
EFFECT: invention enables eliminating side effects, recovering physiological properties of skin and providing high patient's satisfaction upon completion of the treatment.
1 tbl, 1 ex
SUBSTANCE: invention discloses a cream for external treatment of Graham-Little-Piccardi-Lasseur syndrome, which contains lanolin, peach oil and distilled water, and is characterised by that it further contains chloroquine, wherein components of the cream are in a defined ratio given in g%.
EFFECT: inhibiting progression of scarring without marked side effects.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the field of cosmetology, namely to a cosmetic composition for peroral introduction, which contains a combination of lycopene, vitamin C, vitamin E and at least one polyphenol compound, obtained from pine bark, in which the ratio of weight content of polyphenol compound to the sum of weight contents of lycopene, vitamin C and vitamin E constitutes from 0.3 to 0.7, as s single active ingredient.
EFFECT: invention is intended for prevention and/or treatment of wrinkles in the area of eyes and mouth angles, small wrinkles, eye bags and dark circles under eyes.
22 cl, 2 ex, 11 tbl
SUBSTANCE: invention represents a pharmaceutical composition for treating local manifestations of herpes simplex infections and for preventing influenza and acute respiratory viral infections, containing green tea extract and epigallocatechin-3-gallate (EGCG) 70-90 wt %, colloidal silver and a gel-forming base with the ingredients of the composition taken in certain ratio, wt %.
EFFECT: high clinical effectiveness.
6 cl, 8 ex, 5 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: there are presented: using nalbuphine salt in the form of a hydrophilic emulsion suppository for treating moderate to severe pain syndrome, a pharmaceutical composition for the same application in the form of suppositories comprising nalbuphine hydrochloride as an active substance and a hydrophilic emulsion base in the following ratio, g/100 g of the composition: nalbuphine hydrochloride 0.0125-5.00, hydrophilic emulsion base up to 100 g, and a method for preparing the same.
EFFECT: effective and prolonged analgesic action with no laxative action has been shown.
7 cl, 3 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutics and medicine, namely to a soft dosage form in the form of a topical oily gel used in treating purulent skin infections and containing sodium fusidine, methyluracil (dioxomethyl tetrahydropyrimidine), an oily gel base (mineral oil and polyethylene) and additionally hydroxymethyl quinoxaline dioxide.
EFFECT: developing the preparation for treating purulent wounds, degrees 3-4 burns, decubituses and ulcers, possessing the improved antibacterial effect and regenerative action.
2 cl, 8 ex, 2 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to veterinary science and medicine, and may be used to prevent and treat bacterial infections. An antibacterial injectable pharmaceutical composition comprises azithromycin, solvents and/or co-solvents, a preserving agent, and an antioxidant. The antioxidant is presented by ascorbic acid, or sodium ascorbate, or calcium ascorbate, or palmityl ascorbate, or 4-methyl-2,6-ditertbutylphenol, or tertbutylhydroquinone, 2,4,5-trihydroxybutyrophenone, or sodium metabisulphite, or alpha tocopherol, or thioglycerol, or combinations thereof; the preserving agent is presented in the form of benzyl alcohol, parabenes, chloroethanol or combinations thereof; the solvents or co-solvents are organic solvents, including dimethylacetamide, or dimethylsulphoxide, or N-methyl-2-pyrrolidone, or 2-pyrrolidone, or combinations thereof, or combinations of organic solvents with water in the following relations, wt %: azithromycin 5-50, antioxidant 0.1-0.2, preserving agent 1-2, pH regulator up to 5, solvents the rest.
EFFECT: antibacterial injectable pharmaceutical composition of azithromycin possesses a wide spectrum of the antimicrobial action, and is applicable to the intravenous, intramuscular, subcutaneous, intrauterine and intracisternal introduction.
3 cl, 1 dwg, 7 tbl, 11 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutics and represents a combined drug preparation for the local treatment of periodontics, including a complex of metronidazole and chlorhexidine in a combination with sodium fusidine, sweetening agents and a pharmaceutically acceptable gel base in the following proportions, g: sodium fusidine 1.8-2.2; metronidazole 0.9-1.1; chlorhexidine bigluconate (in the form of 20% chlorhexidine bigluconate) 0.42-0.58 in the amount equivalent to chlorhexidine 0.08-0.12; sodium saccharinate 0.1-0.3; monoammonium glycerrhizinate (MM100) 0.006-0.008; aerosil 200 (colloidal silicon dioxide) 5.5-6.0; paraffin oil (Vaselin oil) - the rest up to 100 g.
EFFECT: invention provides creating the therapeutic pharmaceutical composition in the form of gel possessing the antibacterial and anti-inflammatory action with an optimum combination of the ingredients to provide a stable depot of the active substances within an area of inflammation for the purpose of treating infectious-inflammatory periodontics of various aetiologies.
3 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, namely to a method for preparing a therapeutic hydrogel material involving mixing an aqueous solution of sodium alginate and a drug preparation, dispersing a cross-linking agent that is presented by calcium sulphate in glycerol in the concentration of 0.8-2.5%, mixing the dispersion with the prepared mixture of sodium alginate with the drug preparation in ratio 1-2:4-6, placing the prepared product into a tiling pattern and keeping it till form-stable, conducting gamma sterilisation; the formation process involves the mechanical stability measurements with the diametral compression of the formed hydrogel; the hydrogel is considered to be formed once a thickness of the formed hydrogel varies with the diametral compression by 10-30%.
EFFECT: invention provides the wider medical variation of the drug concentrations, preparing high-thixotropy soft hydrogel materials (tablets) easy to administer, including through rectum, preparing the materials that preserve its all their physical-technical and mechanical properties after the gamma sterilisation along with the sterility.
4 cl, 10 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a formulation of a traditional Chinese medicine for treating bronchial asthma, and a method for preparing it. The traditional Chinese medical composition is prepared of pure herbal raw materials, including ephedra herb (Herba Ephedrae), ginkgo seeds (Semen Ginkgo), mulberry bark (Cortex Mori), skullcap root (Radix Scutellariae), bitter apricot seeds (Semen Armeniacae Amarum), pinellia rhinzomes (Rhizoma Pinelliae), perilla fruit (Fructus Perillae), foalfoot blossom (Flos Farfarae), red peony root (Radix Paeoniae Rubra), houttuynia herb (Herba Houttuyniae), trichosanthis root (Radix Trichosanthis), forsythia fruit (Fructus Forsythiae).
EFFECT: traditional Chinese medical composition is effective in treating bronchial asthma.
11 cl, 7 tbl, 12 ex