Ophthalmic compositions with poly(ethylene oxide)-poly(butylene oxide) block copolymers
SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and aims at treating dry eye syndrome, for contact lens disinfection and remoistening. A sterile water-based ophthalmic composition contains poly(ethylene oxide)-poly(butylene oxide) block copolymer of formula (EO)m(BO)n and galactomannan. Herewith, m has an average value of 45, and n has an average value of 9 to 18. Said galactomannan represents guar or its derivative. Besides, presented are a method for treating dry eye syndrome and a method for disinfecting a contact lens with using the above composition. The other embodiment discloses a method for delivering a pharmaceutical agent into the eyes involving the local administration of a formulation containing one or more pharmaceutically active agents and the above composition into the eyes.
EFFECT: using the group of inventions enables ensuring the more effective application of the above composition by providing the additional stability of a lachrymal film of the composition.
19 cl, 6 tbl, 29 dwg, 3 ex
CROSS-REFERENCE TO RELATED APPLICATION
According to United States code, section 35, §119, this application claims priority based on provisional patent application U.S. No.61/223599, filed July 7, 2009, the complete contents of which are incorporated herein by reference.
TECHNICAL field of the INVENTION
The present invention relates, in General, to compositions with ethylene oxide-butylaniline block copolymers and, in particular, to compositions with ethylene oxide-butylaniline block copolymers containing galactomannan, such as guar or guar derivatives.
PRIOR to the INVENTION of the prior art
It is well known the use of polymeric ingredients in the compositions, specifically in ophthalmic compositions for topical administration. Polymeric ingredients generally used in the compositions of the slurries as auxiliary substances for physical stability, helping insoluble ingredients remain in suspension or easily resuspendable. Polymers also impart the desired viscoelastic and rheological characteristics of the compositions of which they are part.
Many polymers used in ophthalmic compositions for topical administration. Such polymers include cellulose polymers such as hydroxypropylmethyl�ellulose, hydroxyethylcellulose and metilgidroxiatilzelllozu. They also include synthetic polymers, such as carboxyvinyl and polyvinyl alcohol. Others include polysaccharides, such as xanthan gum, guar gum and dextran.
In ophthalmic compositions is also used combinations of polymers. It is known that certain combinations of polymers provide a synergistic effect on viscosity and, in some cases, even at the phase transition from liquid to gel. For example, U.S. patent No. 4136173 discloses ophthalmic compositions that contain a combination of xanthan gum and resin carob.
A BRIEF summary of the INVENTION
The present invention relates in certain embodiments to ophthalmic compositions containing ethylene oxide-utilizatsionnyi (EO-BO) block copolymer with the formula (EO)m(BO)nand galactomannan, such as guar or a derivative of guar. The authors of the present invention unexpectedly discovered that the ethylene oxide-butylaniline block copolymers interact with galactomannan in aqueous solution. Aqueous compositions that contain EO-BO copolymers behave as Newtonian fluids, and EO-BO copolymer at low concentrations contributes little to the viscosity of such a composition. However, galactomannan and composition with EO-BO on�present invention synergistically increase the viscosity in comparison with the compositions, containing galactomannan or EO-BO separately. Galactomannan and composition with EO-BO of the present invention possess desirable viscoelastic and interfacial properties, making them suitable for use in ophthalmology, and in particular, to disinfect and re-wetting contact lenses.
Ethylene oxide-butylaniline block copolymers in aqueous solutions are vysokolegirovannye amphiphile. When used in ophthalmic solutions of these non-ionic surfactants on the phase boundary air-water form the elastic layers, which can have a softening effect on the contact lens. In addition, by changing the hydrophobicity (replacement butyleneglycol units) EO-BO block copolymers in solution, it is possible to obtain favorable changes in the elasticity of such solutions.
In a preferred embodiment of the compositions of the present invention contain ethylene oxide-utilizatsionnyi the block copolymer with the formula (EO)m(BO)nwhere m is an integer with an average value of from 10 to 1000, and n is an integer with an average value of from 5 to 1000, and where the galactomannan is a derivative of guar, such as hydroxypropanoic, native guar or hydroxypropanoic galactomannan.
Embodiments of the present invention also include the use of co�positions containing ethylene oxide-utilizatsionnyi the block copolymer and galactomannan, in solutions for disinfecting contact lenses, in the compositions from dry eyes and artificial tears compositions. The present invention also relates to methods of applying these compositions to treat various ophthalmic disorders, including dry eye, glaucoma, ocular hypertension, infection, Allergy and inflammation.
The foregoing brief essence approximately describes the features and technical advantages of certain embodiments of the present invention. Additional features and technical advantages will be described in the subsequent detailed description of the invention. New properties, which are believed to be inherent in the invention will be more apparent from the detailed description of the invention.
BRIEF description of the DRAWINGS
The following drawings are part of the present description and are included to further demonstrate specific aspects of the present invention. The invention will be more clearly under one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
FIGURE 1 shows the scan amplitude for different compositions with EO-BO.
FIGURES 2a-2e show the curves �Jerzy ow for songs with EO-BO and HP-guar.
FIGURES 3a-3e show the curves sweep voltage shift for songs with EO-BO and HP-guar in table 2.
FIGURES 4a-4e show the curves of frequency sweeping for songs with EO-BO and HP-guar in table 2.
FIGURES 5a-5d show the curves of the spatial rheology for songs with EO-BO and HP-guar in table 2.
FIGURES 6a-6b represent the sweeping curves of amplitude and frequency sweeping for songs with EO-BO and HP-guar.
FIGURES 7a and 7b are histograms summarizing the experiments in which we investigated the ability of compositions with EO-BO of the present invention to prevent the capture of polar lipid (FITC-DHPE, FIGURE 7a) and non-polar lipid (NBD-cholesterol, FIGURE 7b) various contact lenses from silicone hydrogel.
FIGURE 8 is a histogram showing the number of non-polar lipid (NBD-cholesterol), which remains on the different lenses made of silicone hydrogel after treatment with compositions containing EO-BO and HP-guar.
FIGURES 9a-9d demonstrate the effectiveness of the cleansing compositions with EO-BO of the present invention in comparison with the carrier.
DETAILED description of the INVENTION
The present invention relates in certain embodiments to ophthalmic compositions which contain an ethylene oxide-utilizatsionnyi (EO-BO) block copolymer � galactomannan, such as guar or a derivative of guar. Ethylene oxide-butylaniline block copolymers of these compositions have the following General formula:
where m is an integer with an average value of from 10 to 1000, and n is an integer with an average value of from 5 to 1000. The block copolymers of the present invention are those that include polyoxyethylene block as the hydrophilic component and Polyoxymethylene block as the hydrophobic component. These blocks can be in the form of a diblock copolymer, which is denoted as EO-BO, tribloc-copolymer, represented as EO-BO-EO or BO-EO-BO, or other configurations of the block. Unless otherwise stated, all references to "EO-BO block copolymers" herein include all of the above forms. These copolymers can also be described using approximate or average values assigned to the corresponding repeating group. For example, (EO)20(BO)5where the average value for oxyethylene group is 20, and the average value for oxybutylene group is 5. The compositions of the present invention, generally contain EO-BO copolymer in a concentration of from 0.001 to 1.0% wt./about. Preferred compositions of the present invention contain EO-BO copolymer in a concentration of from 0.01 to 0.1% wt./about.
Especially p�impactfully are EO-BO diblock copolymers with the following General formula:
where R is selected from the group consisting of hydrogen, methyl, ethyl, propyl and butyl; m is an integer with an average value of from 10 to 1000, and n is an integer with an average value of from 5 to 1000.
Most preferred is the copolymer with the formula (II), where R is methyl; m has an average value of 45; and n has an average value of from 9 to 18.
EO-BO block copolymers used in this invention have a molecular weight in the range from 1000 to approximately 100000 daltons, and more preferably in the range from 1000 to about 15000 daltons.
Maintaining a certain hydrophilic-lipophilic balance (HLB) imparts certain properties to the compositions with EO-BO block copolymers of the present invention. For example, HLB block copolymers used in the compositions of the present invention is directly related to the solubility, wettability and surface activity on the surface of the phase compositions of the present invention.
BO-part of the block copolymer with the formula (I), above, is hydrophobic and primarily responsible for the properties of wettability of the compositions described herein. EO-a part of the copolymer provides compositions hydrophilic properties, but more importantly, this part of the copolymer determines the water rastvorimost� copolymers. Although, in the compositions of the present invention can be used solvents, and in this case, the ratio of EO to share BO is less critical, it is preferable to use copolymers which do not require the use of solvents, since such compounds can disrupt or change the HLB, which in turn could adversely affect the wetting properties of the compositions, resulting in irritation of the eyes, or creating other problems. Thus, preferred copolymers of the above formula (I) are those where there is a predominance of EO-shares over BO-lobes. That is, the variable "m" in the above formulas (I) and (II) is preferably greater than the variable "n". EO-BO block copolymers preferably have a ratio of EO to BO from about 2:1 to about 10:1; the ratio of about 3:1 to about 6:1 is preferred.
EO-BO block copolymers of the present invention can be obtained using synthetic methods known to experts in this field, for example, as described in Nace, V. M., J. Am. Oil Chem. Soc., Vol. 73(1):1-9, 1996; Yang et al., Macromolecules, Vol. 27:2371-2379, 1994; Yang et al., Langmuir, Vol. 11:4703, 1995; Yu et al., Langmuir, Vol. 12:3404-3412, 1996; Chaibundit et al., Langmuir, Vol. 16:9645-9652, 2000; Bedells et al., J Chem. Soc., Faraday Trans., Vol. 89:1235-1242, 1990; and Kelarakis et al., Macromolecules, Vol. 31:944-946, 1998, the full contents of which are incorporated into this description by reference. Hig�these EO-BO block copolymers can also be obtained by application or adaptation of known methods, described in U.S. patents №№ 2828345 (Spriggs) and 2174761 (Schuette et al.), the contents of which are fully incorporated into the present description by reference. Additional synthetic methods can be studied at Ketelson et al. (patent application U.S. No. 11/953654), the contents of which are incorporated herein as references in full.
Basically, the above EO-BO block copolymers can be synthesized using well-characterized polymer of polyethylene glycol (PEG) through a controlled addition of oxybutylene to the primary hydroxyl group of the PEG polymer. For example, EO-BO diblock copolymer (EO)45(BO)10can be obtained according to the following General reaction scheme:
Other options chemical structure of the blocks can also be obtained using readily available techniques and methods that are well known in the art. For example, to get tribloc copolymers of the form (EO)m(BO)n(EO)myou can use the following reaction process:
EO-BO block copolymers of the present invention may also be functionalized using a specific end groups for certain surface reactions covalent bonding of the polymer with the surface, or get a new polymeric material. EO-BO block copolymers�trollers, which can be used in the present invention is not limited in structure or molecular weight as long as the block copolymers are soluble in aqueous solutions, and non-toxic to the eye tissue in those concentrations, which are described in this document.
As used herein, the term "galactomannan" refers to the polysaccharide derivative of the above natural gums or similar natural or synthetic gums containing group, mannose or galactose, or both groups, as main structural components. Several types of water-soluble, which can be used in the present invention are, as a rule, derivatives of guar gum powder, gum carob and Tara gum. Galactomannans of the present invention can be obtained from various commercial sources and by synthetic methods known to experts in this field. In preferred embodiments, the galactomannan is hydroxypropanoic (HP-8A or HP-guar), obtained from Rhodia, Inc. Other galactomannans as non-limiting examples include native guar and hydroxypropanoyl galactomannan produced in accordance with the technological processes of co-pending patent applications U.S. No. 61/220859, p�this on June 26, 2009 and No. 61/150215, filed February 5, 2009, the contents of which are fully incorporated herein by reference. The compositions of the present invention, generally contain galactomannan in a concentration of from 0.01 to 2.0% wt./about. Preferred compositions of the present invention contain galactomannan in a concentration of from 0.05 to 0.25% wt./about.
In addition to EO-BO block copolymer and the galactomannan, the compositions of the present invention optionally contain one or more additional components. Such components as non-limiting examples include a means to give toychest, preservatives, chelating means, buffer means, surfactants, co-solvents and antioxidants. Other components used in certain embodiments, represent solvents, stabilizers, substances that increase the ease of consumption, polymers, emollients, substances that regulate pH, and/or lubricants. Components that can be used in a specific kompoziciyah of the present invention include water, mixtures of water and solvents can be mixed with water, such as C1-C7-aliphatic alcohols; vegetable oil or mineral oil containing from 0.5 to 5% non-toxic water-soluble polymers, natural products�s, such as alginates, pectins, tragakant, gum, gum karaya, xanthan gum, carrageenin, agar and acacia; starch derivatives such as starch acetate and hydroxypropylmethyl; and also the fat synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, a simple ether of polyvinylether, polyethylene oxide, preferably cross-linked polyacrylic acid, and mixtures of these products.
In addition to EO-BO block copolymer and the galactomannan, the compositions of the present invention may contain compounds with antimicrobial or preservative properties. Suitable antimicrobial agents as non-limiting examples include those generally used in solutions for the care of contact lenses or other ophthalmic solutions, such as polyquaternium-1, which is a polymeric Quaternary ammonium compound; myristamide dimethylamine ("MAPDA"), which is a N,N-dialkyl, N'-alkyl, Ethylenediamine; guanidine derivatives, such as polyhexamethylene of biguanide ("PHMB") or polyaminopropyl of biguanide (PAPB); perborate, such as sodium perborate, and peroxides, such as hydrogen peroxide. Additional anti-microbial agents that can be used in the present invention also include aminopyrine, opisan�e in U.S. patent No. 6664294, the content of which is fully incorporated into the present description by reference. Preferred additional antimicrobial agents are polyquaternium-1, MAPDA and aminopyrine named in the U.S. patent No. 6664294 as "Compound number 1".
Suitable antioxidants as non-limiting examples include sulfites, ascorbates, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
In addition to EO-BO block copolymer and the galactomannan, the compositions of the present invention can contain one or more surfactants. Surfactants used in the compositions of the present invention may be cationic, anionic, nonionic or amphoteric. Preferred surfactants are neutral or nonionic surfactants that may be present in an amount up to 5% wt./about. Surfactants that can be used in specific embodiments of the present invention, as non-limiting examples include polyethylene glycol, ethers or esters of fatty acids, polyoxyethylene-polyoxypropylene block copolymers of ethylene diamine (for example, poloxamine, such as Tetronic 1304 or 1107), polyoxypropylene-polyoxyethyleneglycol�ü non-ionic block copolymers (e.g., poloxamer, such as Plutonic F-127), and polymers of the p-isooctylphenyl of phenolformaldehyde (e.g. Tyloxapol).
In certain embodiments of the present invention suitable co-solvents include glycerin, propylene glycol and polyethylene glycol.
Buffer means that you can enter in the composition of the present invention, as non-limiting examples include alkali metal salts, such as potassium carbonate or sodium acetates, borates, phosphates and citrates, and weak acids such as acetic acid and boric acid. The preferred buffer means are borates of alkali metals such as sodium borate or potassium. You can also use other means of regulating pH, such as inorganic acids and bases. For example, you can use hydrochloric acid or sodium hydroxide in concentrations suitable for ophthalmic compositions. The above-described buffer means are present, generally in amounts of from about 0.1 to about 2.5% wt./vol., preferably from about 0.5 to about 1.5% wt./about.
The compositions of the present invention are preferably isotonic or slightly hypotonic, and generally have an osmolality in the range 210-320 mOsm/kg, and preferably have an osmolality in �the range of 235-300 mOsm/kg. You may need substance that regulates the correct tonicity to bring osmolality of the composition to the desired level. Substances that regulate the correct tonicity, as non-limiting examples include sodium chloride, glycerol, sorbitol or mannitol.
To apply for disinfection of contact lenses, disinfectants that can be used, as non-limiting examples include halogenide, halogenated amino, bis-amines and specific preservatives described above. The amount of disinfectant required to achieve the desired disinfecting activity can be determined by experts in this field. The concentration necessary to achieve the desired disinfecting activity while maintaining acceptable safety and toxic properties herein designated as "an effective amount". Effective number has an antimicrobial effect, sufficient to meet the generally accepted standards of activity, such as the EN ISO 14729:2001 Ophthalmic optics - care Products contact lenses - Microbiological requirements and test methods for products and protocols for hygiene control contact lenses.
For ophthalmic application of the present invention, the pH of the composition may be difficult to� in ophthalmological acceptable range from 3.0 to 8.0. Preferred ophthalmic compositions are prepared using a buffering system that maintains pH of the composition is from about 3.0 to about 8,0.
In specific embodiments, compositions of the present invention are suitable for topical application to the eye of mammals. For example, for injection into the eye, the composition may be a solution, suspension, gel, water-in-oil "emulsion "oil-in-water or ointment. Preferred compositions for ophthalmic administration include an aqueous solution in the form of drops. The term "water" generally refers to the aqueous composition, where excipient is >50%, more preferably > 75% and in particular > 90% by weight of water. These drops can be entered from the ampoule with a single dose, which may preferably be sterile and, thus, the composition is not desired bacteriostatic components. Alternatively, the droplets can enter the bottle for repeated administration, which preferably may contain a device that removes the preservative of the composition at the time of its filing, such devices known in this field.
In certain embodiments, the topical applications for ophthalmology, the compositions of the present invention can include one or more substitutes of tears. A number of substitutes SL�h is known in this field, as non-limiting examples include Monomeric polyols, such as glycerol, propylene glycol and ethylene glycol; polymeric polyols such as polyethylene glycol; esters of cellulose, such as methylcellulose, sodium carboxymethylcellulose and hydroxypropyl cellulose; dekstrana, such as dextran 70; vinyl polymers such as polyvinyl alcohol; and carbomer, such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P. Ophthalmic compositions of the present invention for topical application generally have a viscosity of 0.5 to 100 centipoise, preferably 0.5 to 50 centipoise, and most preferably 1-20 GPa. Such a relatively low viscosity ensures that the product will be comfortable, will not cause fogging, and will be easily handled during production, transportation and packaging.
The compositions of the present invention can also be used for delivery of pharmaceuticals in the eye. Such pharmaceuticals as non-limiting examples include the against glaucoma agents, anti-angiogenic agents, anti-infective agents, antiinflammatory agents, agents of growth factors, immunosuppressive agents, and anti-allergic agents. Agents against glaucoma as non-limiting examples include beta-blockers, such as Metaxa�l and levobetaxolol; the carbonic anhydrase inhibitors, such as brinzolamide and dorzolamide; prostaglandins, such as travoprost, bimatoprost and latanoprost; serotonin agonists; agonists muscarine; dopamine agonists. Antiangiogenic agents as non-limiting examples include anecortave acetate (RETAANETM, AlconTMLaboratories, Inc. of Fort Worth. Tex.) and inhibitors of receptor tyrosine kinase inhibitors (RTKi). Anti-inflammatory agents include, without limitation nasteride and steroid anti-inflammatory drugs, such as triamcinolone actinide, suprofen, diclofenac, Ketorolac, nepafenac, rimexolone and tetrahydrocortisol. Agents of growth factors include EGF, or VEGF. Antiallergic agents as non-limiting examples include olopatadine and epinastine, antagonists of H1 and H4 receptors (such as those described in WO 2010/030785 Borchardt et al, incorporated herein by reference in its entirety).
The following examples are provided to further illustrate selected embodiments of the present invention.
|Sodium hydroxide/Hydrochloric acid||To bring the pH to 7.0|
|Purified water||As necessary|
Conducted experiments to study the rheology of compositions with EO-BO and guar of the present invention. These experiments included experiments on the rheology volume, including steady state flow, and sweep in frequency and shear stress. Also were used to define the spatial parameters of rheology and the rheology at the phase interface.
Experiments on the rheology of the volume was performed using a rheometer with controlled shear stress (AR 2000ex, TA Instruments, Inc.). The measurement system consisted of a 40 mm acrylic 2° cone and plate with a sample volume of 0.58 ml. keeping a temperature of 25°C +/-0.1°C, the system for measuring covered to prevent evaporation of the solutions. For experiments with steady-state regime of the flow (SSF), a tool created reg�interface shear stress, which in turn led to the result of viscosity against shear rate". Spent two dynamic test: scan the oscillation of the shear stress, and scan the oscillation frequency. Scan the oscillations in the shear stress maintains a constant frequency of the solution during the measurement range of the shear stress. Scan the oscillations in the shear stress measurement of G' (elastic modulus/storage) and G” (viscosity module/losses). From this data we can determine the region of linear viscoelasticity (LVR). LVR is an area in the scan voltage shift obtained from G', where the solution retains its elasticity, G', in the range of shear stress. In these experiments, get the value of relative elasticity, tan(δ)=G”/G'. Scan the oscillation frequency remains constant shear stress inside LVR during the measurement frequency range. This measurement can also determine the G', G” and tan(δ). Scan the oscillation frequency indicates how well the solution keeps its structure.
Experiments on the rheology of the phase separation was performed using an optical device to a generator of oscillating drops (OCA20, Dataphysics Instruments) equipped with a piezoelectric device and an amplifier, which controlled oscillation drops. A drop suspended in a cell with temperature control�ture and humidity, at the end of the needle is made of stainless steel with an inner diameter of 1.65 mm, was observed using a CCD camera (768×576 pixels) at 500 images per second. Technology generator oscillating drops (ODG) characterizes the mechanical strength of the films on the analysis of the drop shape at the specified frequency in the range of amplitudes. The amplitude changes the volume and shape of the droplets and, thus, the surface area of.
Control parameters for experiments with the regime of steady currents were as follows:
• All solutions before the experiment had the same rheological background
• 40 mm 2° acrylic cone:
- volume of 0.75 ml
- 60 µm slit
• Double concentric cylinder:
- volume of 6.8 ml
- a gap of 500 microns
• The temperature was set at 25ºC
• Established equilibrium within 10 minutes after installation of the geometry
- Pre-shift 10 sec-1within 10 sec
• Torque is set from 0.1 MISP to 100 MISP
- 0,1 MISP was the lower limit
- 100 MISP and was not taken into account
• 5 points per decade; 5 min equilibrium at each point; triple measurement at 5% deviation
• Geometry covered with a flat lid 60 mm, to prevent evaporation
• Sweep shear stress (torque)
- Dean from 0.1 cm to 100 Dynes-cm in Isho�Noi phase for all studied solutions
Frequency set to 0.1 Hz
• Frequency sweeping
- from 0.01 Hz to 10 Hz
- Torque set at 100 Dynes-cm
• Scan time
- Pre-shear of 100 sec-1within 10 seconds
- Used a frequency of 0.1 Hz and a torque of 100 Dynes-cm
|Plate diameter||6.00 mm|
|The initial height of the sample||3,01 mm|
|The final height of the specimen||of 13.32 mm|
|Sample volume||80 µl|
|The total hencky strain||1,49|
|The initial compression ratio||1,0|
|The final compression ratio||4,44|
|Effective speed||0,21 mm/s|
|Time stretching||50 MS|
|Method||High-speed digital method|
|The frequency of taking samples||10000 Hz|
|Duration of presentation sample||1.0 sec|
|Note: if the duration of presentation of the sample was longer than 1.0 sec, the frequency of taking readings corrected for optimal measurement.|
The following is a description of the parameters and equipment used for the experiment on the rheology at the phase boundary with the application of an oscillating bubble. For the experiment with oscillating bubble was used OCA20 generator with oscillating drops. The following is a description of the parameters used in the experiment for each song:
|Method||The measurement of the volume of the oscillating cantilevered drops|
|The time of establishing the equilibrium bubble||3.5 h|
|Step of the iteration||20 (logarithmic)|
|Amplitude||0,003 mm-0.3 mm|
|Step duration||40 h|
|Images for step||1000|
Before each run the system was checked and standardized by confirming the surface tension of water at of 72.5 mn/m at 25°C air. A quartz cuvette was half-filled with purified water and placed below drops out of sight of the camera. This was to prevent the loss of water from the droplets during equilibration and throughout the experiment. Before each experiment with oscillating bubble, bubbles were equilibrated for a period of not less than 3.5 hours.
Tables 1 and 2 below detail the composition, was studied in experiments on EO-BO rheology of the phase separation and rheology EO-BO/guar, respectively. All songs from table 2 also contain up to 1.0% boric acid, 0.35% of NaCl, and 0.001% of polyquaternium-1 and have a pH of 7.5.
(% wt./% about.)
|Purified water (QS=100 ml)||QS||QS||QS||QS|
(% wt./% about.)
|EO45BO18||-||-||-||-||-||-||-||-||-||0,2||0,5||The time of rupture,||0,131||0,247||0,323||0,361||0,342||amount of 0.118||of 0.146||0,140||0,180||0,104||was 0.138|
|Viscosity (CP)@ 10,0 c-1||10,54||10,59||11,00||12,70||11,22||6,80||5,20||6,12||6,09||4,80||a 4.64|
FIGURE 1 shows the scan amplitude for songs with EO-BO from table 1. The graphs show that the contribution of the elastic component at the interface air-water these songs with EO-BO increases as the size of the structural units of BO increases from BO10to BO18.
FIGURES 2a-2e show the curves of the regime established thread for songs with EO-BO and HP-guar in table 2. The graphs show that the shear thinning decreases as the concentration increases EO-BO block copolymer. Composition with EO45-BO9-11 have similar viscosity profiles compared with the composition containing only HP-guar. Composition with EO45BO14-18have profiles thinning shear, similar to that in compositions containing only HP-guar, however, their viscosity is lower than compositions containing only HP-guar.
FIGURES 3a-3e show the curves sweep voltage shift for songs with EO-BO and HP-guar in table 2. The curves show that all the studied compositions are predominantly viscous (G") solutions with elasticity (G', structure). Composition with EO45BO9-11have a structure similar to that of composition containing only HP-guar, with similar areas of linear viscoelasticity. Composition with EO45BO14-18have some structure, but have a region of linear viscoelasticity, which rapidly decrease with increasing shear rate.
FIGURES 4a-4e show the curves of frequency sweeping for songs with EO-BO and HP-guar in table 2. Composition with EO45BO9-11have a structure similar to the composition which only contains HP-guar throughout the frequency sweep. Composition with EO45BO14-18have some structure, which rapidly decays with increasing frequency.
FIGURES 5a-5d show the curves of the spatial rheology for songs with EO-BO and HP-guar in table 2. Curves �shows, that song with EO45BO9-11long-time film break than the composition containing only HP-guar. Composition with EO45BO14-18by the time of the rupture, similar to that in compositions containing only HP-guar. Composition with EO45BO9-11also have a higher spatial viscosity compared with the composition containing only HP-guar. Composition with EO45BO14-18have a spatial viscosity similar to that of the composition containing only HP-guar. Observed the influence of compositions with EO-BO to other galactomannans, such as native guar. As shown below in table 3, EO-BO increases the gap films for compositions containing HP-guar and native guar.
|Sample||Concentration||pH||The tear film|
|A||0,2% HP8A/0,04% EO-BO||7,5||0,09264|
|C||0.2%�active guar/0,04% EO-BO||7,5||0,10002|
|D||0,2% native guar/0,04% EO-BO||7,5||0,08642|
|E||0,2% native guar/0,2% EO-||7,5||0,09602|
|F||0,2% native guar||7,5||0,09042|
|A||0,2% HP8A /0,04% EO-BO||8,0||0,21142|
|C||0,2% native guar/0,04% EO-BO||8,0||0,32863|
|D||0,2% native guar/0,04% EO-BO||8,0||1,39927|
|E||0,2% native guar/0,2% EO-BO||8,0||2,12335|
|F||0,2% native guar||8,0||1,67517|
FIGURES 6a-6b show the sweeping curves of amplitude and frequency sweeping for songs with EO-BO and HP-guar in table 2. The scan amplitude and frequency, track number with EO45BO11and EO45BO16was predominantly elastic at the phase boundary air-water. However, EO45BO16was more structured in comparison with EO45BO11.EO-BO keeps the structure at the interface air-water in the investigated concentrations compared with guar.
The above rheological characteristics show that the compositions of the present invention are well suited for use in ophthalmology, and specifically for local use in ophthalmology. In particular, compositions with EO-BO and guar can provide additional stability to the tear film when used in compositions for the treatment of dry eye.
The compositions of the present invention were tested for their ability (i) to prevent the deposition of lipids and proteins on the lenses from silicone hydrogel and (ii) clear lenses lipid and protein deposits. Table 4 is a list of the examined lens, and Tables 5 and 6 for a list of tested compositions.
|Pure Vision™||Bausch and Lomb®|
|Focus Night&Day™||Ciba Vision®|
|N - [3-dimethylaminopropyl] tetradecanamide||0,0006||0,0006||0,0006|
|N - [3-dimethylaminopropyl] tetradecanamide||0,0007||0,0008||0,0007||0,0008|
The histograms in the FIGURES 7a and 7b summarize the experiments examined the ability of compositions with EO-BO of the present invention to prevent the capture of lenses from silicone hydrogel from TABLE 4 polar lipid (FITC-DHPE, FIGURE 7a) and non-polar lipid (NBD-cholesterol, FIGURE 7b). The results show that the composition (Lot 13990-23A and 23C, TABLE 6) is particularly effective to prevent the seizure of non-polar lipid in all studied lenses.
FIGURE 8 shows �the histogram, showing the number of non-polar lipid (NBD-cholesterol), remaining on the lenses from table 4 after cleaning the different studied compositions. The chart shows that the investigated composition according to the present invention (14336-11C, TABLE 5) removes deposits of non-polar lipid with contact lenses of silicone hydrogel better than other studied compositions, in 3 of the 4 lenses.
FIGURES 9a-9d show that the composition of the present invention (14336-11C, TABLE 5) effective for clearing test lenses from table 4 from different proteins (lysozyme, lactoferrin, beta-lactoglobulin).
Essentially, the experimental results show that the compositions of the present invention effective to clean the lens and can prevent the capture of non-polar lipids. The compositions are also particularly effective for the removal of lens deposits non-polar lipids.
The present invention and its implementation options were described in detail. However, the scope of the present invention is not limited to specific variants of implementation of any process, product, composition of matter, compounds, methods, and/or steps disclosed in the description. Various modifications, substitutions and variations can be made to disclosed material within the entity and/or essential characteristics of the present invention. Thisway, the person skilled in the art will easily understand from the description that subsequent modifications, substitutions and/or variations, representing essentially the same function, or leading essentially to the same result as the variants of implementation, described herein, can be used according to the same related to the options of implementing the present invention. Thus, the following formula of the invention encompasses in its scope modifications, substitutions and variations of processes, products, compositions, substances, compounds, methods, and/or steps described herein.
1. Sterile aqueous ophthalmic composition comprising ethylene oxide-utilizatsionnyi (EO) block copolymer with the formula (EO)m(BO)nand galactomannan, where m has an average value of 45 and n has an average value of from 9 to 18.
2. A composition according to claim 1, where m has an average value of 45 and n has an average value of from 9 to 11.
3. A composition according to claim 1, wherein the galactomannan is guar or its derivative.
4. A composition according to claim 3, where the specified guar or a derivative of guar is selected from the group consisting of:
native guar, hydroxypropylamino and hydroxypropylamino of galactomannan.
5. A composition according to claim 1, where the specified SW IN the block copolymer is present in a concentration of from 0.001 to 1.0% wt./about.
6. A composition according to claim 1, where the uke�this SW IN the block copolymer is present in a concentration of from 0.01 to 0.1% wt./about.
7. A composition according to claim 1, wherein the galactomannan is present in a concentration of from 0.01 to 2.0% wt./about.
8. A composition according to claim 1, wherein the galactomannan is present in a concentration of from 0.05 to 0.25% wt./about.
9. A method of treating dry eye, comprising topical administration of an ophthalmic composition, where said composition contains an ethylene oxide-utilizatsionnyi (EO) block copolymer with the formula (EO)m(BO)nand galactomannan, where m has an average value of 45 and n has an average value of from 9 to 18.
10. A method according to claim 9, where m has an average value of 45 and n has an average value of from 9 to 11.
11. A method according to claim 9, where the specified galactomannan is guar or its derivative.
12. A method according to claim 11, where the specified guar or a derivative of guar is selected from the group consisting of:
native guar, hydroxypropylamino and hydroxypropylamino of galactomannan.
13. A method according to claim 9, where the specified SW IN the block copolymer is present in a concentration of from 0.001 to 1.0% wt./about.
14. A method according to claim 9, where the specified SW IN the block copolymer is present in a concentration of from 0.01 to 0.1% wt./about.
15. A method according to claim 9, where the specified galactomannan is present in a concentration of from 0.01 to 2.0% wt./about.
16. A method according to claim 9, where the specified galactomannan is present in a concentration of from 0.05 to 0.25% wt./about.
17. Method of disinfection of contact lenses, including�th immersing the lens in an antimicrobial composition, containing ethylene oxide-utilizatsionnyi (EO) block copolymer with the formula (EO)m(BO)nwhere m has an average value of 45 and n has an average value of from 9 to 18, and galactomannan, for a time period sufficient to disinfect the lenses.
18. The method of delivery of pharmaceuticals in the eye, comprising the topical administration to the eye a composition comprising one or more pharmaceutically active agents, ethylene oxide-utilizatsionnyi (EO) block copolymer with the formula (EO)m(BO)nwhere m has an average value of 45 and n has an average value of from 9 to 18, and galactomannan.
19. A method according to claim 18, where the pharmaceutically active agent(funds) chosen/selected from the group consisting of agents against glaucoma, anti-angiogenic agents, anti-infective agents, antiinflammatory agents, agents, growth factor, immunosuppressive agents and anti-allergic agents.
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and aims at treating macular degeneration in a mammal. A pharmaceutical composition for treating macular degeneration in a mammal contains an effective amount of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α isopropyl ester. The above ophthalmic composition is presented in the form of eye drops, which are sterile, preservative-free as a single-use dosage form. What is also provided is a method of treating macular degeneration in a mammal that involves administering an effective amount of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α isopropyl ester into an individual in need thereof.
EFFECT: using declared group of inventions provides effective treatment of macular degeneration in a mammal.
11 cl, 1 tbl, 2 dwg, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.
EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.
12 cl, 3 tbl, 21 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of formula I, wherein R1 and R2 are identical or different and specified in an alkyl or alkenyl hydrocarbon chain; the R3 group values split by lipase are specified in the patient claim. R4 and R5 are independently hydrogen or C1-C7alkyl; R6 represents hydrogen or C1-C7alkyl; and R7 and R8 are independently hydrogen or C1-C7alkyl. The invention also refers to using compounds of formulas ,
which are introduced into the mammalian biological system and increase the cell concentrations of specific sn-2 substituted ethanolamine-plasmalogens.
EFFECT: compounds are applicable in treating or preventing the age-related disorders associated with high membrane cholesterol, high amyloids and low plasmalogens, such as neurodegeneration, cognitive disorder, dementia, cancer, osteoporosis, bipolar disorder and vascular diseases.
11 cl, 18 dwg, 7 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to biotechnology. What is presented is a recovered human antibody or its antigen-binding fragment, which specifically binds to human angiopoietin-2 (hAng-2), but does not substantially binds to hAng-1 characterised by the presence of CDR variable heavy and light chain domains. What is described is a pharmaceutical composition on the basis of a therapeutically effective amount of the antibody. Disclosed are: variants of the recovered antibody or its antigen-binding fragment in producing drug preparation for treating a patient suffering various diseases including a tumour. Described are the versions of the methods of treating various diseases.
EFFECT: using this invention provides the antibody highly specific to human angiopoietin-2 (hAng-2) with an affinity constant of approximately 10-11, which does not substantially bind to hAng-1, that can find application in treating various diseases related to hAng-2 hyperactivity.
19 cl, 35 tbl, 3 dwg, 13 ex
SUBSTANCE: invention refers to medicine, particularly to ophthalmopathy, and can be used in treating endothelial-epithelial corneal dystrophy. That is ensured by de-epithelisation, 12-o'clock corneal incision and splitting, administration of a biologically active substance into a stromal pocket of the cornea. The biologically active substance is poludan-activated autoplasma. Before the epithelisation is completed, a soft contact lens is placed on the cornea. The operation is followed by instillations of ciprofloxacin, diclofenac 6 times a day and infusions of cornegel.
EFFECT: method provides reducing the intraoperative injuries and the length of patients' treatment, including by local (intrastromal) autocytokinotherapy.
SUBSTANCE: treating postoperative corneal erosions following pterygium removal. That is ensured by postoperative instillations of drug preparations for corneal erosion. Additionally, the final stage of pterygium removal operation involves administering ozone-oxygen mixture in the concentration of 2 mg/l in an amount of 0.5 ml subconjunctivally. The injection is repeated in the same concentration and amount on the following postoperative day. The method increases the operation effectiveness by reducing postoperative complications and negative symptoms in the patient, including by a compensatory increase of antioxidant enzyme activity, reducing tissue and recovering metabolic processes in the involved tissues, reducing a probability of coarse cicatrisation in the operation region.
EFFECT: method is easy and accessible to implement.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound presented by formula , or their pharmaceutically acceptable salt, which can find application for treating or preventing ophthalmic diseases.
EFFECT: invention refers to the pharmaceutical compositions and methods of treating the ophthalmic diseases with the use of the above compound.
13 cl, 7 dwg, 7 tbl, 4 ex
SUBSTANCE: method involves corneal impregnation with 0.1% riboflavin and ultraviolet exposure at a wave length of 365-375 nm for 30 min. Before impregnation, the cornea is coated with 40% glucose kept on the corneal surface for 9-11 min; residual glucose is removed, and the glucose-treated corneal surface is coated with 0.1% riboflavin for 30 min.
EFFECT: eliminating postoperative complications, reducing the length of the patients' rehabilitation, and achieving the high functional results of the operation.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the pharmaceutical industry and represents an ophthalmic solution containing riboflavin and vitamin E for the UV-A rays protection of the internal structures of an eyeball and for treating keratoconus by transepithelial crosslinking.
EFFECT: invention provides extending the range of products for the UV-A rays protection of the internal structures of the eyeball and for treating keratoconus by transepithelial crosslinking.
9 cl, 10 dwg
SUBSTANCE: simulating this pathology is accompanied by pharmacological preconditioning. That is ensured by using Nicorandil in a single dose of 0.86 mg/kg of body weight which is introduced intragastrically through a probe in the form of a starch solution into a laboratory animal. Ischemia of the retina is simulated 30 minutes later by delivering mechanical pressure of 110 mm Hg on an anterior eye chamber for 30 minutes.
EFFECT: method provides the pronounced correction of ischemic ocular injuries.
1 ex, 1 tbl
SUBSTANCE: group of inventions concerns a method for preparing Sostakovsky balsam containing mixing vinyl butyl ether and butyl alcohol, heating a reaction mass while stirring continuously, feeding a catalyst after achieving the required temperature, decontaminating the prepared polymer, pouring out the polymer heated to 50-70°C into a container through a multilayer filter; the above group also concerns the therapeutic agent possessing the wound-healing, bacteriostatic and analgesic properties and prepared by the above method.
EFFECT: higher yield and purity of the produced preparation as compared to the similar methods with preserving the pharmacological properties inherent to the given preparation.
5 cl, 1 ex
SUBSTANCE: method for preparing a medical gel for erythrocyte and leukocyte separation involves mixing polyisobutylene, chlorinated paraffin, silicon dioxide and propylene glycol hexane dioic acid in a certain environment to prepare an end product having a density required to use the above product as the medical gel.
EFFECT: method enables separating erythrocytes and leukocytes from plasma, keeping blood plasma in its natural composition with no loss of its constituent proteins and change in the concentration of its constituent vitamins and hormones.
SUBSTANCE: what is described is a composition for preparing a dosage form having prolonged action and containing drug preparations with radioprotective activity: Mexidol, Dimexidum, urea, methyluracil, sodium deoxyribonucleate, as well as a water-soluble polymer or a mixture of polymers specified in a group: sodium alginate, pectin, chitosan salt, water, and a substance or a mixture of substances having antiradical properties, and specified in a group consisting of sea buckthorn, bilberry, glycerol, polyethylene glycol, with the following ratio of ingredients, wt %: thickening polymer 1.0-8.0; pharmacological agent in a therapeutically effective amount; substances having antiradical properties 0.5-6.0; distilled water - the rest.
EFFECT: higher degree of intact tissue protection against radiation damages.
8 ex, 2 tbl
SUBSTANCE: uterine arteries are embolised, and methotrexate is administered intra-arterially, while a gestational sac is evacuated with a vacuum excochleator assisted with a transabdominaal ultrasonography. The uterine arteries are embolised using Embosphere® and HepaSphere™ microspheres. Methotrexate is administered intra-arterially from a primary blood supply of the gestational sac in a dose of 25 mg with embolysate microparticles using HepaSphere™ microparticles.
EFFECT: method provides the complete block of the blood supply of the gestational sac ensured by the distal and reliable embolisation, the target action of methotrexate on trophoblast tissue that in turn enables reducing the length of vacuum aspiration of the gestational sac in two times, avoiding the potential development of life-threatening bleeding accompanying the gestational sac evacuation, reducing the side effects of the treatment, and preserving the patient's reproductive function and life.
3 dwg, 2 ex
SUBSTANCE: invention refers to medicine, namely to traumatology and biotechnology, and may be used for the biocompatible polymeric structure formation in bone tissues. That is provided by a puncture approach to a filled cavity in the bone tissues. That is followed by filling the cavity with a polymeric gel compound containing 55-97.7 wt % of the biocompatible polymer polylactide of a particle size of 50 to 100 mcm, 0.3-45 wt % of magnetic nanoparticles of ferric oxide of a particle size of 10 to 100 nm, the gelling agent maltodexrin in the amount of 0.5 to 50 wt % of the weight of mixed polymer and magnetic nanoparticles, as well as distilled water in the amount of 0.5 to 100 wt % of the weight of a dry mixture of the polymer, magnetic nanoparticles and gelling agent. A solid three-dimension structure is formed. That is accompanied with heating the compound throughout by exposing to an alternating magnetic field at frequency 500 kHz and amplitude 500 E for 3-5 minutes. Where appropriate slow down the process of heating the compound, it is additionally exposed to a direct magnetic field at amplitude 1000 E applied either to the whole formed volume, or locally depending on the problem to be solved.
EFFECT: method enables forming the biocompatible three-dimension structure in the specified cavity of the bone tissue with minimum surgical intervention.
SUBSTANCE: eyelid care is performed daily twice a day for one month in the form of a 1-2-minute Blepharowipe stupe. That is followed by a 1-2-minute eyelid self-massage with Blepharogel 1 or Blepharogel 2. Systane Balance artificial tear drops are instilled into a conjunctival cavity every 4 hours 3 times a day. The instillations are alternated with eye blinking exercises for 15 seconds 3 times a day. The therapeutic course is repeated one month later.
EFFECT: recovered functional state of the lipid layer of the tear film with an increase in the protective function of tears and relevant reduction of the clinical manifestations of the degenerative and inflammatory processes in the eyelids, conjunctiva and cornea due to an interaction of the procedures of the method each of which enhances the effect of the following one.
2 cl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a medical gel for erythrocyte and leukocyte separation, and may be used in preparing plasma to be used in plasmolifting technique. The gel contains, wt %: the gelling agent - polyisobutylene - 58.5 - 59.5; the dissolving agent - chlorinated paraffin - 19.5 - 20.5; the chemically and biologically inert filler - silicon dioxide - 13.0 - 14.0; the plasticising agent - propylene glycol adipic acid. The gel is used to prepare plasma for erythrocyte and leukocyte separation by centrifugation.
EFFECT: gel enables preparing the thrombocyte-rich plasma containing no erythrocytes and leukocytes, with maintaining its natural composition, without loss of proteins and vitamin and hormone concentration variations.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a recovered imidised biologically compatible polymer functionalised by an imide group. The above polymer is selected from the group consisting of polyethylene oxide, partially or completely hydrolysed by polyvinyl alcohol, polyvinylpyrrolidone, polyethyloxazoline, polyoxypropylene oxide block copolymers (poloxamers and meroxapol), polyethylene oxide and poloxamine copolymer, carboxymethyl cellulose and hydroxyalkylated cellulose, polypeptides, polysaccharides, carbohydrates, polysaccharose, hyaluronic acid, dextran, heparin sulphate, keratan sulphate, chondroitin sulphate, heparin, alginate, gelatin, collagen, albumin, ovalbumin, complex polyphosphoesters, polylactides, polyglycolides, polycaprolactones, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, polymaleic acids, polyamino acids, polyvinyl alcohol, polyvinylpyrrolidone, polyhydroxy cellulose, chitin, chitosan, and copolymers, ternary copolymers, or combinations or mixtures of the aforementioned materials. Also, the invention refers to a composition for a tissue adhesive, a medical device and a pharmaceutical composition.
EFFECT: invention represents additionally modified or functionalised imidised polymers.
9 cl, 2 ex, 20 dwg
SUBSTANCE: invention relates to medicine, namely to surgery, traumatology and orthopedics and can be used for treatment of early paraprosthetic infection in endoprosthetics of hip joint. For this purpose performed are multiple sanitising processing of wound, during each of which clinical-laboratory monitoring of wound process is carried out, encrectomy is performed. Dislocation of hip endoprosthesis component into wound is carried out, stability of fixation of endoprosthesis components is estimated. In case of stable fixation wound lavage with aseptic solution is performed in volume not less than 2 l with pulsing jet. Wound and endoprosthesis bed are filled with antiseptic with 15 minute exposure. Hip component of endoprosthesis is reset. Wound is tightly tamponed with sorption bandage material based on polyacrylate, wound is tightly sutured. Sanitising processing of wound is performed with one day interval. When signs of regeneration in wound, absence of microflora growth in bacteriological test, normalisation of laboratory blood parameters are achieved, delayed secondary suture of wound is performed.
EFFECT: method ensures stopping of infection process without application of washing drainages, preservation of maximal volume of soft tissues for wound covering, makes it possible to performed delayed secondary suture and preserve endoprosthesis stability.
SUBSTANCE: invention refers to nanotechnology of new materials applicable in biology, veterinary science and medicine, particularly for laser hyperthermia of new growths. What is presented is a method differing from known ones by agent concentrations, pH values of a reaction mixture, and particle surface functionalisation. At the first stage, gold spherical particles of the diameter of 1-3 nm used as a templates for the further growth of non-spherical particles are synthetised. At the second stage, gold is additionally reduced by ascorbic acid on the particles in cetyl trimethyl ammonium bromide in an acid medium (pH=1). At the third stage, cetyl trimethyl ammonium bromide molecules on the particle surface are substituted by polyethylene glycol for reducing biotoxicity of gold nanorods. The method uses the ingredients taken in specific molar ratios. What is also presented is a thermal sensitiser which is produced by the method above and representing a gold nanorod suspension. The rods are 30-45 nm long, 9-12 nm wide and coated by polyethylene glycol molecules.
EFFECT: invention provides higher stability and reproducibility of the gold nanorod synthesis with biotissue infrared absorption, as well as reduced toxicity of the thermal sensitiser.
2 cl, 6 dwg
SUBSTANCE: this invention aims at pharmaceutical compositions and methods for making these compositions containing a number of controlled-release particles. At least one assembly of said particles comprises a nucleus containing weakly basic drug substance, an alkaline buffer layer above the nucleus, and a controlled-release coating. The weakly basic drug substance contains at least one nitrogen-containing fragment with pKa from approximately 5 to approximately 14, with a solubility from at least 200 mg/ml at room temperature in an aqueous solution at pH approximately pH 1.2-6.8 and solubility of no more than approximately 10 mg/ml at pH 8 and more. The controlled-release coating contains a water-insoluble polymer. The pharmaceutical composition also contains rapidly degrading microgranules. This invention also aims at pharmaceutical dosage forms containing orally degrading tablets, classical tablets and capsules, as well as methods for making them.
EFFECT: invention provides the sustained release of the weakly basic drug substance in the small intestine.
65 cl, 1 dwg, 1 tbl, 7 ex