Low-viscous highly flocculated triamcinolone acetonide suspensions for intravitreal injections

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of medicine, in particular to ophthalmology. Medicinal compositions for intravitreal injections and methods of treating ophthalmological disorders are disclosed. Medicinal compositions represent suspensions on the basis of low-soluble medication, such as triamcinolone acetonide. Compositions of suspensions have relatively low viscosity and are easily extracted via needle of 27- or 30-gauge needle, but are highly flocculated and can be easily redispersed.

EFFECT: group of inventions ensures improvement of vitreos body visualisation in the course of vitrectomy, treatment of ophthalmological disorders.

20 cl, 5 ex

 

The technical field

The present invention relates to compositions for injection, used for the treatment of diseases or pathological conditions of the eye. More specifically, the present invention relates to compositions of the suspensions, which have low viscosity and high (i.e. free) flocculated. The compositions of the slurries contain steroid triamcinolone or other poorly soluble drug connection.

The level of technology

Containing triamcinolone acetonide composition for injection is available for sale for many years. Commercial products include the Kenalog®-10 injection (suspension of triamcinolone acetonide for injection, USP) and the Kenalog®-40 injection (suspension of triamcinolone acetonide for injection, USP) from Bristol-Myers Squibb Co. These products contain 10 mg/ml or 40 mg/ml triamcinolone acetonide, respectively. According to the package insert use of Kenalog-40 injection approved for some intramuscular or intra-articular injection. If the doctor oral therapy is impossible or temporarily undesirable, in some cases shown intramuscular application of Kenalog-40 injection in endocrine diseases, rheumatic diseases, collagenosis, dermatologic diseases, allergic States, ophthalmic is deseases, gastrointestinal diseases, respiratory diseases, hematologic disorders, neoplastic diseases and edema. Specific approved ophthalmic indications are severe chronic allergic and inflammatory processes involving the eye, such as eye shape Herpes zoster;

iritis; iridocyclitis; chorioretinitis; diffuse posterior uveitis and chorioidea, optic neuritis; sympathetic ophthalmia; and inflammation of the anterior segment. The kenalog-40 injection is indicated for intra-articular or intrabursal injection and for injection into the synovial sheath of the tendon as a short-term concomitant therapy (to overcome the patients acute episode or attack) in the following conditions: synovitis in osteoarthritis; rheumatoid arthritis; acute and subacute bursitis, acute gouty arthritis, epicondylitis, acute nonspecific tenosynovitis; and post-traumatic osteoarthritis.

There is now a growing use of Kenalog®-40 injection for treatment of macular edema. In this case, the product is administered by injection into the vitreous body of the eye of a patient suffering from diabetic macular edema. In some cases, the physician or pharmacist is subjected to product processing in an attempt to remove the preservative is present in the composition of Kenalog-40 on the I injection supplied by Bristol-Myers Squib Co. (for example, benzyl alcohol), because the preservative may irritate the vitreous body and the tissues in the posterior segment of the eye. In addition, a commercially available product can be used immediately after shaking, in order to avoid the formation of sludge; instructions to the package insert States the following: "to prevent the formation of sludge in the syringe injection be conducted immediately after shaking the bottle and selection of the drug".

Accordingly, the necessary improved composition of the suspension of triamcinolone acetonide, which is suitable for ocular injection, not quickly deposited, and which is suitable for injection through a thin needle, which gives the sewn turned injections (e.g., needle size 27 or 30).

Summary of the invention

The present invention relates to improved compositions suspension of triamcinolone acetonide, which are especially suitable for eye injections. Improved compositions of aqueous suspensions possess excellent characteristics of the deposition, easy resuspended with a small shake, do not contain preservatives, as well as easily and gently entered when using the needle 30-th size. In addition, the composition of the suspension according to the present invention may in the end be sterilized by autoclaving. HDMI is the suspension are also suitable for slightly soluble drugs in addition to triamcinolone.

Among other factors, the present invention is based on the discovery that it is possible to obtain the composition of the suspension of triamcinolone acetonide, which has improved characteristics of deposition relative to currently available compositions triamcinolone acetonide a Kenalog-40 injection. The present invention is also based on the discovery that the composition of the suspension of triamcinolone acetonide containing a relatively low amount of surface-active substances, has excellent flocculating properties relative to currently available compositions of Kenalog-40 injection, at the same time as being easier to handle during manufacturing processes, transfer and filling, and easy to extract (from the bottle) with needles from 27 th to 30-th size.

Detailed description of the invention

Unless otherwise stated, all amounts of ingredients are expressed as a percentage of weight to volume.

In a preferred embodiment of the invention the composition of the aqueous slurry according to the present invention consist essentially of triamcinolone acetonide, carboxymethylcellulose, Polysorbate 80, pharmaceutically acceptable chloride salt to summarize toychest, a buffering agent and water for injection.

Triamcinolone acetonide before the hat is a steroid, which can be obtained by known methods and which is available for sale in microtrenching form. Triamcinolone acetonide should be crushed so that the average particle diameter was 3 to 10 μm. Methods of grinding such as grinding in a ball mill, known, and they can be used to satisfy these requirements, size and distribution of particles. The composition of the suspension according to the present invention contain from 35 to 40 mg/ml (3.5 to 4.5%) of triamcinolone acetonide, preferably 40 mg/ml (4.0%) of triamcinolone acetonide.

In addition to the triamcinolone acetonide composition of the suspension according to the present invention contain 0,45-0,55% sodium carboxymethylcellulose ("CMC"). Preferably the compositions contain 0.5% CMC. CMC with different viscosity of commercially available from various companies. For example, Hercules Inc. supplies CMC low (7LF PH), medium (7MF PH) and high (7HF PH) viscosity. CMC included in the compositions of the present invention, preferably has a low viscosity, so that the viscosity of a 2%solution of CMC in water at 25°C is 25 to 50 centipoise (measured using Brookfield viscometer LVT spindle CF-42 at 60 rpm).

The compositions of the present invention have a viscosity of 2 to 12 centipoise, preferably 2-9 JV and most preferably 2-8 SP. They slowly settled and easy resuspending who I am. This relatively low viscosity ensures easy handling of the product during the manufacturing processes, transfer and filling and easy retrieval (from the bottle) with needles on the 27th or the 30th of the size.

In General, the pharmaceutical compositions of the suspensions contain a surfactant for wetting and distribution of the particles of the medicinal product, and the amount of surfactant is usually higher than the amount required for complete wetting of the individual particles, since this excess contributes to a better distribution of the particles. However, it can be difficult to obtain a high degree of flocculation.

The number of Polysorbate 80 used in the Kenalog-40, is 0.04%. However, it was found that at a much lower concentration of surface-active substances, for example, of 0.015%, the particles form loose flakes, thereby causing a high degree of flocculation. Low viscosity and a high degree of flocculation of the compositions of the present invention ensures that they are easily re-distributed or resuspended under mild shaking. Therefore, the compositions of the present invention contain a lower concentration of surfactant relative of Kenalog-40. More specifically, the compositions of the present invention with the, may contain 0,002-0,02% of Polysorbate 80. Preferably the compositions contain 0.01-0.02% Polysorbate 80, and most preferably the compositions contain 0.015% Polysorbate 80.

Used in the present description, the "degree of flocculation" means the ratio of the final volume of sediment (namely in the form of a percentage of the total) to the concentration of particles. For example, the suspension with the concentration of particles (drugs) 4% and final volume of sludge 8% will have a degree of flocculation 2. Similarly, the composition of the suspension with a concentration of 4% and final volume of sludge 20% will have a degree of flocculation 5, and a similar composition with a final volume of sludge 40% will have a degree of flocculation 10.

The ultimate volume of sediment is the volume of sediment (namely the percentage of the total) after prolonged storage at room temperature and does not change significantly after additional storage time. The ultimate volume of sediment quickly achieved for low viscosity suspensions, for example, for the period of time from several hours to several days, but for systems with medium or high viscosity education final volume of sediment may take days or weeks.

The amount of sludge can be determined as follows: 10 ml of the composition of the suspension is placed in a graduated cylinder, 10 ml, and record the volume of sludge as a function of time. For example, the EU and the sludge level reaches 1 ml graduated cylinder, it corresponds to the volume of sludge to 10%. If the residue does not change significantly with additional storage time, then its volume is used as a final volume of sediment.

The compositions of the present invention have a degree of flocculation above 5, preferably above 6, and most preferably above 7.

The compositions of the present invention also contain one or more pharmaceutically acceptable chloride salts as agents for leading toychest. The preferred chloride salt is sodium chloride. In the most preferred embodiment of the invention the compositions contain sodium chloride, potassium chloride, calcium chloride and magnesium chloride. Agents for leading toychest are present in a total amount sufficient to provide in the compositions of the present invention, the osmolality of 250-350 mOsm. In one embodiment of the invention the compositions contain 0.4 to 0.6% sodium chloride, 0.05-0.1% potassium chloride, 0.04 to 0.06% of calcium chloride and 0.01 to 0.04% of magnesium chloride.

If necessary, the suspension composition of the present invention also contain an agent to bring the pH, such as NaOH or HCl to bring the pH of the compositions to pH 6-7,5. The composition of the suspension contain pharmaceutically acceptable buffering agent to maintain the pH of the compositions within 6-7,5. Fittingly, the buffering agents include sodium acetate and sodium citrate. Preferably the compositions contain a combination of sodium acetate and sodium citrate.

The composition of the suspension according to the present invention preferably Packed in single dose containers, such as glass or plastic ampoules. The composition of the suspension can also be Packed in syringes or cartridges.

Used in the present description, the term "injection in the posterior segment of the eye include, but are not limited to, injection into the vitreous body, the injection of the sclera or under the sclera and injection outside of the vitreous body and under teanaway capsule.

In one embodiment, the present invention relates to a method for the treatment of macular edema, including, but not limited to, diabetic macular edema or occlusion retinal vein, including occlusion of the Central retinal vein and its branches, which includes an injection in the posterior segment of the eye of the composition of the suspension described above. In another embodiment, the present invention relates to a method for the treatment of postoperative inflammation, which includes an injection in the anterior segment of the eye of the composition of the suspension described above. In yet another embodiment, the present invention relates to a method of treating ophthalmic diseases or pathological conditions of the posterior segment of the eye, including but not limited to, mA is warnow degeneration, which includes an injection in the posterior segment of the eye of the composition of the suspension described above. For those embodiments in which the treatment of diseases or pathological conditions, the compositions of the present invention preferably by injection (for example, in the vitreous body or in other parts of the posterior segment of the eye, or in front of the camera) for injection initial dose of 4 mg of triamcinolone acetonide (for example, 100 microlitres composition of the suspension 40 mg/ml), if necessary with the introduction of subsequent doses during treatment.

In yet another embodiment, the present invention relates to a method for improving visualization of the vitreous body during vitrectomy. In this embodiment, the composition of the present invention is administered intravitreally for introduction from 1 to 4 mg of triamcinolone acetonide (e.g., 25-100 microlitres composition of the suspension 40 mg/ml).

In yet another embodiment, the present invention relates to compositions suspensions of slightly soluble drugs in addition to triamcinolone. Used in this description of "slightly soluble drug is a drug having a solubility at 22°C less than 1 mg/ml at pH 7.5 in phosphate-buffered saline. The composition of the suspension consists essentially of LABORAS Voronovo medicinal compounds, carboxymethylcellulose, Polysorbate 80 or tyloxapol, pharmaceutically acceptable chloride salt to summarize toychest, optionally, a buffering agent, optionally, the agent to bring the pH and water for injection. The composition of the slurry have a pH from 6 to 7.9, viscosity 2-12 SDR and the degree of flocculation above 5. Preferably the composition of the suspension consists essentially of:

a) from 0.5 to 8.0% (weight/volume) slightly soluble drug, and the drug has a volumetric average diameter of 3-10 μm;

b) 0,45-0,55% (weight/volume) sodium carboxymethylcellulose;

C) 0,002-0,02% (weight/volume) Polysorbate 80 or tyloxapol;

g) one or more pharmaceutically acceptable chloride salts as agents for leading toychest;

d) water for injection;

e) optionally, a buffer agent and

g) optional agent to summarize the pH to 6-7,9.

The preferred concentration of Polysorbate 80 or tyloxapol is 0,002-0,01% for compositions with a concentration of slightly soluble drug compounds in the range of 0.5-2%. The preferred concentration of Polysorbate 80 or tyloxapol is 0,01-0,02% for compositions with a concentration of slightly soluble drug compounds in the range of 2-8%.

In one embodiment of the invention slightly soluble drugs may be medicines for the treatment of macular edema, occlusion of retinal vein, geographic atrophy, dry age-related macular degeneration or wet age-related macular degeneration. One example of such slightly soluble drug is tandospirone.

The present invention also relates to a method of treatment of ophthalmologic disorders, including introduction using intravitreal injections of the composition of the suspension consisting essentially of:

a) from 0.5 to 8.0% (weight/volume) slightly soluble drug, and the drug has a volumetric average diameter of 3-10 μm;

b) 0,45-0,55% (weight/volume) sodium carboxymethylcellulose;

C) 0,002-0,02% (weight/volume) Polysorbate 80 or tyloxapol;

g) one or more pharmaceutically acceptable chloride salts as agents for leading toychest;

d) water for injection;

e) optionally, a buffer agent and

g) optional agent to summarize the pH to 6-7,9.

Some embodiments of the invention are illustrated in the following examples.

Example 1

The composition of Kenalog®-40 shown in table 1.1 below. It contains 4% triamcinolone acetonide and 0.04% Polysorbate 80. The viscosity of this suspension is about 14 centipoise.

The particle size for several batches was measured using laser diffraction (Microtrac® S3000), and he is can be found in table 1.2. The median particle size of different batches of Kenalog-40 varies from 13 to 22 μm.

The force required to extract the suspension of Kenalog®-40 through a needle G30x13 mm, attached to a tuberculin syringe 1 ml, are shown in table 1.3. The results show that the suspension of Kenalog-40 scored the needle 30-th size. The value of the required strength varied significantly and was high. Clogging of the needle occurred due to the large particle size of the suspension.

It was determined that the composition of the suspension Kenalog®-40 has a finite amount of sediment approximately 14% and therefore has a degree of flocculation of 3.5. As a result, this suspension is only weakly flocculated relative compositions of the suspensions of the present invention.

Table 1.1
The composition of KENALOG-40
ComponentThe KENALOG-40, % (weight/volume)
Triamcinolone acetonide4
Sodium carboxymethylcellulose0,75
Polysorbate 800,04
Benzyl alcohol : 0,99
Sodium chloride0,75
Sodium hydroxide and/or hydrochloric acidfrom 5.0 to 7.5
Water for injectionup to 100%

Table 1.2
The particle size for the six parties of KENALOG-40, measured using Microtrac
The lot number (date)Particle size (microns)x10(Microtrac)Particle size (microns)x50(Microtrac)Particle size (microns)x90(Microtrac)
5L01206
(10/2007)
5,020,250,0
6B19016
(02/2008)
3,513,638,6
6D16625
(04/2008)
4,321,157,4
6F11285
(04/2008)
3,4 13,6of 40.9
6F15845
(04/2008)
5,621,754,0
6D18800
(04/2008)
4,215,741,6

Table 1.3
The power required for takeoff suspension of Kenalog-40
(Syringe 1 ml with needle 30GAx13 mm)
Description compositionThe average load, lbs (standard deviation)Maximum load, pounds-force
The kenalog, 40 mg/ml, party 6F11285, good till 04/085,33
(4,457)
10,2 (needle stuck in 4 of 10 cases)

Example 2

To prepare the suspension of triamcinolone acetonide with various concentrations of Polysorbate 80, but without CMC, as shown in table 2.1. Volumetric average particle size of triamcinolone acetonide used in these compositions was 5-6 μm (measured using a Microtrac® S3000).

For these compounds we studied the formation of sediment, placing the images is about 10 ml each in a separate graduated cylinders, 10 ml and registering the amount of sludge as a function of time. As a control investigated the Kenalog®-40. The results are presented in table 2.2. These results show that 4%formulations of triamcinolone with concentrations of Polysorbate 80 is less than 0,02% have greater final volume of sediment. For these compositions, the amount of sludge stabilized per day and did not change within 7 days. The degree of flocculation for these samples ranged from 9.5 to 13.5, indicating that the samples were highly flocculated. However, compounds with the concentration of Polysorbate 80 0.02% and above formed a compact layer of sediment at the bottom of the graduated cylinder. The volume of sediment in these cases was less than 10% and the degree of flocculation was about 2. Thus, the compounds with the concentration of Polysorbate 80≥0,02% were not highly flocculated.

Table 2.1
Used to study the formation of a precipitate of the composition of the suspension of triamcinolone acetonide without agents that increase the viscosity
CompositionABCDEF
Triazines is on acetonide 4%4%4%4%4%4%
Polysorbate 800,002%0,005%0,01%0,015%0,02%0,025%
Sodium chloride0,64%0,64%0,64%0,64%0,64%0,64%
Potassium chloride0,075%0,075%0,075%0,075%0,075%0,075%
Calcium chloride (dihydrate)0,048%0,048%0,048%0,048%0,048%0,048%
Magnesium chloride (uranyl)0,03%0,03%0,03%0,03% 0,03%0,03%
Sodium acetate (trihydrate)0,39%0,39%0,39%0,39%0,39%0,39%
Sodium citrate (dihydrate)0,17%0,17%0,17%0,17%0,17%0,17%
HydroxideTo sumTo sumTo sumTo sumTo sumTo sum
sodium and/or hydrochloric acidpH to 6.8pH to 6.8pH to 6.8pH to 6.8pH to 6.8pH to 6.8
Water for injectionup to 100%up to 100%up to 100%up to 100%up to 100%up to 10%

Table 2.2
The study of the formation of a precipitate of Kenalog-40 and suspension of triamcinolone acetonide without CMC at various concentrations of Polysorbate 80
TimeThe precipitate in each measuring cylinder 10 ml (volume of sediment in %)
CompositionThe kenalog-40AndInWithDEF
Polisar-baht 800,04%0,002%0,005%0,01%0,015%0,02%0,025%
The beginning (0 min)Homogeneous: 10 mlHomogeneous: 10 mlHomogeneous: 10 mlHomogeneous: 10 mlHomogeneous: 10 mlHomogeneous: 10 ml Homogeneous: 10 ml
1 hourSediment: 7,4 ml (74%)Sediment: 5,2 ml (52%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)Sediment: 3.8 ml (38%)Sediment: 7,4 ml (74%)Precipitate: to 7.2 ml (72%)
2 hoursSediment:
5.0 ml (50%)
Sediment: 5,2 ml (52%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)Sediment: 3.8 ml (38%)Sediment: 4.8 ml (48%)Sediment: 4,2 ml (42%)
4 hoursSediment: 1,4 ml (14%)Sediment: 5,2 ml (52%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)Sediment: 3.8 ml (38%)Sediment: 1.0 ml (10%)Sediment: 1.0 ml (10%)
6 hoursSediment: 1,4 ml (14%)Sediment: 5.0 ml (50%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)Sediment: 4,0 ml (40%) Sediment: 0.8 ml (8%)Sediment: 0.8 ml (8%)
1 daySediment: 1,4 ml (14%)Sediment: 5.0 ml (50%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)Sediment: 4,0 ml (40%)Sediment: 0.8 ml (8%)Sediment: 0.8 ml (8%)
2 daysSediment: 1,4 ml (14%)Sediment: 5.0 ml (50%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)Sediment: 3.8 ml (38%)Sediment: 0.8 ml (8%)Sediment: 0.8 ml (8%)
5 daysSediment:Sediment:Sediment:Sediment:Sediment:Sediment:Sediment:
of 1.4 ml (14%)5.0 ml (50%)of 5.4 ml (54%)with 5.2 ml (52%)of 3.8 ml (38%)0.8 ml (8%)0.8 ml (8%)
7 daysSediment: 1,4 ml (14%)Sediment: 5.0 ml (50%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)Sediment: 3.8 ml (38%)Sediment: 0.8 ml (8%)Sediment: 0.8 ml (8%)
The degree flocculi testing3,512,513,5139,522

Example 3

Composition 4%of the energy suspension of triamcinolone acetonide 0.015% Polysorbate 80, and various concentrations of CMC are described in table 3.1 below. Volumetric average particle size of triamcinolone acetonide used in these compositions was 5-6 μm (measured using a Microtrac® S3000).

For these compounds we studied the formation of precipitates by placing samples of 10 ml each in a separate graduated cylinders, 10 ml and registering the amount of sludge as a function of time. The results are presented in table 3.2. The degree of flocculation in each case was >10. Thus, these compositions are typical examples of highly flocculated songs really the image the structure.

Table 3.1
Composition triamcinolone injection with CMC
CompositionGHIJ
Triamcinolone4%4%4%4%
Polysorbate 800,015%0,015%0,015%0,015%
Carboxymethylcellulose sodium (7LFPH)0%0,25%0,5%0,75%
Sodium chloride0,64%0,64%0,64%0,64%
Potassium chloride0,075%0,075%0,075%0,075%
Calcium chloride (dihydrate)0,048% 0,048%0,048%0,048%
Magnesium chloride (uranyl)0,03%0,03%0,03%0,03%
Sodium acetate (trihydrate)0,39%0,39%0,39%0,39%
Sodium citrate (dihydrate)0,17%0,17%0,17%0,17%
Sodium hydroxide and/or hydrochloric acidTo bring the pH to 6.8To bring the pH to 6.8To bring the pH to 6.8To bring the pH to 6.8
Water for injectionup to 100%up to 100%up to 100%up to 100%

tr>
Table 3.2
The study of the formation of sediment in suspension of triamcinolone acetonide 0.015% Polysorbate 80 at various concentration of the x CMC
TimeThe precipitate in each measuring cylinder 10 ml (volume of sediment in %)
TrackGHIJ
Polysorbate 800,015%0,015%0,015%0,015%
Carboxymethylcellulose sodium,
7LFPH concentration
0%0,25%0,5%0,75%
The beginning (0 min)Homogeneous: 10 mlHomogeneous: 10 mlHomogeneous: 10 mlHomogeneous: 10 ml
5 minutesSediment: 9,0 ml (90%)Sediment: 9,8 ml (98%)Precipitate: to 9.9 ml (99%)Sediment: 0
10 minutesPrecipitate: to 8.2 ml (82%)Sediment: 9,8 ml (98%)Sediment: 9,6 ml (96%)Sediment: 9,8 ml (98%)
20 minutesSediment: 6,4 ml (64%)Sediment: 9,0 ml (90%)Precipitate: to 9.2 ml (92%)Sediment: 9,6 ml (96%)
30 minutesSediment: 6,4 ml (64%)Precipitate: to 8.2 ml (82%)Sediment: 9,0 ml (90%)Precipitate: to 9.3 ml (93%)
21 hoursSediment: 4.8 ml (48%)Sediment: 5.6 ml (56%)Sediment: 5,2 ml (52%)Sediment: 5,4 ml (54%)
24 hoursSediment: 4.8 ml (48%)Sediment: 5.6 ml (56%)Sediment: 5,4 ml (54%)Sediment: 5,2 ml (52%)
The degree of flocculation121413,513

Example 4

The composition of the suspension, typical compositions according to this invention, are described in table 4.1 below. This composition has a 4% triamcinolone acetonide and 0.015% Polysorbate 80. The viscosity of this composition is about 5 CPS (Brookfield Viscometer LVT, spindle CF-42 the ri 60 rpm).

The results of determination of particle size typical of a lot of this composition is presented in table 4.2 (the measurement was performed on the analyzer Microtrac® S3000). The median particle size is 5.6 μm.

The force required to extract the composition through a needle G30x13 mm, attached to a tuberculin syringe 1 ml, given in table 4.3. The results show that the required power was significantly lower than the force required for the suspension of Kenalog-40 (see example 1, table 1.3). In this case, there was no clogging of the needle 30-th size.

We also carried out to study the formation of sludge, described in example 2, and the composition It had a degree of flocculation about 13, indicating a highly flocculated composition.

Table 4.1
Composition of triamcinolone acetonide injection
ComponentCompositionmg/ml
Triamcinolone acetonide4,040
Polysorbate 800,0150,15
Carboxymethylcellulose is the atrium 0,55,0
Sodium chloride0,555,5
Potassium chloride0,0750,75
Calcium chloride (dihydrate)0,0480,48
Magnesium chloride (uranyl)0,030,3
Sodium acetate (trihydrate)0,39a 3.9
Sodium citrate (dihydrate)0,171,7
Sodium hydroxide and/or hydrochloric acidTo bring the pH to approximately 6,8To bring the pH to approximately 6,8
Water for injectionup to 100%to 1 ml

Table 4.2
The particle size for a typical party of suspension of triamcinolone acetonide FID 110300
CompositionParticle size (microns)x10(Microtrac)Particle size (microns)x50(Microtrac)Particle size (microns)x90(Microtrac)
To1,65,610,8

Table 4.3
The force required for selection of a sterile suspension of triamcinolone acetonide
(Syringe 1 ml with needle 30GAx13 mm)
CompositionThe average load, lbs (standard deviation)Maximum load, pounds-force
To0,55
(0,205)
1,1 (the needle is not clogged)

Example 5

Composition 1%and 8%suspension of tandospirone shown in table 5.1 below.

Table 5.1
The composition of the suspension of tandospirone
Component Composition MComposition N
Tandospirone1,08,0
Polysorbate 80 or tyloxapol0,0050,02
Carboxymethylcellulose sodium0,50,5
Sodium chloride0,80,8
Dibasic sodium phosphate dodecahydrate0,250,25
Sodium hydroxide and/or hydrochloric acidTo a pH of about 7.5±0,2To a pH of about 7.5±0,2
Water for injectionup to 100%up to 100%

1. The aqueous suspension composition, in particular suitable for ocular injection, where the specified composition of the suspension contains no preservative, has a pH from 6 to 7.5, a viscosity 2-12 SDR and the degree of flocculation is above 5, and consists essentially of:
a) 3,5-4,5% (wt./about.) triamcinolone acetonide and triamcinolone acetonide has a volumetric average diameter of 3-10 μm;
b) 0,45-,55% (wt./about.) sodium carboxymethylcellulose;
C) 0,002-0,02% (wt./about.) Polysorbate 80 or tyloxapol;
g) one or more pharmaceutically acceptable chloride salts as agents for leading toychest in General sufficient for the osmolality of the composition of the suspension 250 to 300 mOsm;
d) a buffering agent;
e) water for injection; and
g) optional agent to summarize the pH to 6-7,5.

2. The composition of the suspension according to claim 1, where the composition of the suspension is the degree of flocculation above 6.

3. The composition of the suspension according to claim 2, where the composition of the suspension is the degree of flocculation is above 7.

4. The composition of the suspension according to claim 1 where the concentration of triamcinolone acetonide is 4% (wt./vol.).

5. The composition of the suspension according to claim 1, where sodium carboxymethyl cellulose has a molecular weight such that a 2% (wt./about.) a solution of sodium carboxymethylcellulose in water at 25°C has a viscosity of 25-50 SDR.

6. The composition of the suspension according to claim 1, where the concentration of sodium carboxymethylcellulose 0.5% (wt./vol.).

7. The composition of the suspension according to claim 1, where the concentration of Polysorbate 80 is 0,01-0,02% (wt./vol.).

8. The composition of the suspension according to claim 7, where the concentration of Polysorbate 80 is of 0.015% (wt./vol.).

9. The composition of the suspension according to claim 1, containing sodium chloride, potassium chloride, calcium chloride and magnesium chloride.

10. The composition of the suspension according to claim 9, containing 0.4 to 0.6% (wt./about.) chloride intothree is, of 0.05-0.1% (wt./about.) potassium chloride, 0,04-0,06% (wt./about.) calcium chloride and 0.01 to 0.04% (wt./about.) of magnesium chloride.

11. The composition of the suspension according to claim 1, where the buffer agent contains sodium acetate and sodium citrate.

12. The composition of the suspension according to claim 1, where the composition of the suspension has a viscosity 2-9 SDR.

13. The composition of the suspension 12, where the composition of the suspension has a viscosity 2-8 SDR.

14. The aqueous suspension composition, in particular suitable for ocular injection, where the specified composition of the suspension contains no preservative, has a pH of 6 to 7.9, viscosity 2-12 SDR and the degree of flocculation is above 5, and consists essentially of:
a) 0,5-8,0% (wt./about.) slightly soluble drug, and the drug has a volumetric average diameter of 3-10 μm;
b) 0,45-0,55% (wt./about.) sodium carboxymethylcellulose;
C) 0,002-0,02% (wt./about.) Polysorbate 80 or tyloxapol;
g) one or more pharmaceutically acceptable chloride salts as agents for leading toychest;
d) water for injection;
e) optionally, a buffering agent; and
g) optional agent to summarize the pH to 6-7,9.

15. The composition of the suspension 14, where slightly soluble drug selected from the group consisting of medicines for the treatment of macular edema;
medicines for the treatment of occlusion retinal vein;
medicines the La treatment of geographic atrophy;
medicines for the treatment of dry age-related macular degeneration; and medicines for the treatment of wet age-related macular degeneration.

16. The composition of the suspension 14, where slightly soluble drug is tandospirone.

17. The composition of the suspension 14, where the composition of the suspension contains Polysorbate 80.

18. A method of treating ophthalmic disorders, including introduction using intravitreal injections of the composition of the suspension consisting essentially of:
a) from 0.5 to 8.0% (wt./about.) slightly soluble drug, and the drug has a volumetric average diameter of 3-10 μm;
b) 0,45-0,55% (wt./about.) sodium carboxymethylcellulose;
C) 0,002-0,02% (wt./about.) Polysorbate 80 or tyloxapol;
g) one or more pharmaceutically acceptable chloride salts as agents for leading toychest;
d) water for injection;
e) optionally, a buffering agent; and
g) optional agent to summarize the pH to 6-7,9.

19. The method according to p, in which the composition of the suspension contains Polysorbate 80.

20. Method for improving visualization of the vitreous body during vitrectomy, including the introduction using intravitreal injections of the composition of the suspension consisting essentially of:
a) from 3.5 to 4,5,0% (wt./about.) slightly soluble drug cf is DSTV, having a volumetric average diameter of 3-10 μm;
b) 0,45-0,55% (wt./about.) sodium carboxymethylcellulose;
C) 0,002-0,02% (wt./about.) Polysorbate 80 or tyloxapol;
g) one or more pharmaceutically acceptable chloride salts as agents for leading toychest;
d) water for injection;
e) optionally, a buffering agent; and
g) optional agent to summarize the pH to 6-7,9.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of ophthalmology. Described is application of compositions for reduction of intraocular pressure, which contain antocyanoside or including it extract, proantocyanidine or including it extract or their combinations.

EFFECT: group of inventions ensures effective application of compositions for reduction of intraocular pressure in patient.

30 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology and can be used for treatment of post-LASIK keratectasia. For this purpose in space under epithelial-stromal corneal flap round recess is made from periphery to optic zone (in central zone of cornea), into which hypotonic riboflavin solution is introduced. When thickness of cornea 400 mcm and more is reached, space is filled with 0.1% riboflavin solution on 20% solution of dextran T 500 until cornea is saturated with riboflavin. After that, ultrasonic irradiation of cornea is carried out with wavelength 365 nm with intensity 3 mW/cm2 for 30 min fractionally - 6 cycles 5 each 5 minutes long. During irradiation of cornea with ultrasonic waves riboflavin solution is instilled on cornea each 2-3 minutes, additionally riboflavin solution is introduced into recess under epithelial-stromal corneal flap each 5 minutes for constant support of riboflavin solution volume in intrastromal space.

EFFECT: method ensures increase of cornea thickness to required level due to creation of conditions for fast saturation of cornea with riboflavin solution, acceleration of healing process with reduction of risk of postoperative complications development to minimum.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of intraocular pressure reduction and to a method of pain control involving the administration of a therapeutic compound representing , or its tautomer or stereoisomer forms wherein X represents NH; n is equal to 2 or 3; Ra, Rb, Rc and Rd represent stable functional groups independently consisting of: 0 to 4 carbon atoms, 1 to 9 hydrogen atoms; and Re represents H or C1-4alkyl. Furthermore, the invention refers to a compound represented by formula , or to its tautomer or stereoisomer form.

EFFECT: new compound is prepared; besides, the known compounds to be applied in pain and glaucoma control are studied.

8 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to veterinary science, and concerns treating corneal diseases in dogs. For this purpose, mesenchymal cord and placental stem cells received after easy human delivery are used. The mesenchymal stem cells are introduced retrobulbarly in saline solution 1-2 ml containing 0.075-0.20×106 cell/kg. The cells are introduced 1-2 times annually.

EFFECT: method provides the effective treatment of corneal diseases in dogs by creating the depot stem cells in a close proximity to the lesion.

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology, and is intended for treatment of inflammatory and trophic cornea diseases. For this purpose silicone-hydrogel soft contact lens, covered from inner surface by silico-dried amnion, is placed on cornea. Amnion with diameter smaller than lens diameter is used. Amnion is fixed on lens by means of polyacrylamide film, saturated with medication. As such means, used is antibacterial, anti-inflammatory, regenerating medication.

EFFECT: method ensures elimination of amnion dislocation under lens and reduction of time of corneal defect epithelisation, which increases treatment efficiency.

3 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly ophthalmology, and aims at conservative treatment of dacryostenosis. Ofloxacin ophthalmic gel is introduced into a lachrymal duct. Ofloxacin ophthalmic gel 3ml is introduced every second day, 8-10 times.

EFFECT: method provides recovered patency of the lachrymal ducts and prevented recurrent postoperative stenosis following dacryorhinocystostomy, including due to mechanical dilatation of the duct by means of the gel the physical characteristics of which differ from those of tears.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a multidose ophthalmic composition containing prostaglandin as a therapeutic ingredient, mannitol or sorbitol 0.15-0.5 wt/vol %, propylene glycol or glycerol 0.2-1.8, borate 0.25-0.5 wt/vol %, an antimicrobial preserving agent 0.0003-0.003 wt/vol % representing a polymer quaternary ammonium compound and water. Said composition has pH 6.4-7.2 and is benzalconium chloride free. Besides, the invention refers to the use of said ophthalmic composition for preparing a drug for treating glaucoma, eye infections, allergies and inflammations.

EFFECT: preparing the ophthalmic composition which exhibits improved antimicrobial preserving activity and improved buffer properties.

16 cl, 8 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology, and may be used for treating, stabilising and/or preventing macular degeneration. The therapy involves introduction of a therapeutically effective amount of the C5 agent in a combination with a VEGF agent in an individual in need thereof. The C5 agent is bound with C5 complement and has the sequence SEQ ID N0:4 or SEQ ID N0:67.

EFFECT: invention provides an additive or synergetic effect ensured by the combination that leads to improved visual acuity especially in the patients suffering wet age-related macular degeneration (AMD) as compared with the VEGF monotherapy.

67 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to ophthalmology and can be applied for instillation anaesthesia in cavity eye operations on anterior segment of eye, in particular in phacoemulsification of cataract with implantation of IOL. For this purpose two hours before operation instillations of viceine or vita-iodurol in dose 2 drops into conjunctival cavity of operated eye are carried out every 15 minutes, eight times in total. One hour before operation simultaneously started is instillation of local anesthetic inocaine or alcaine in dose 2 drops every 10 minutes, five times. Interval of instillation between vitaiodineurol or viceine and local anesthetic constitutes five minutes.

EFFECT: method ensures increased anaesthesia efficiency due to increase of cornea permeability and reduction of operation and post-operation complications due to reduction of toxic action of anesthetic.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and described a water-based liquid composition for activation of intraocular penetration of a compound of formula (I) containing an amide compound, and an agent forming an ionic pair. What is also described is a method for activation of intraocular penetration of the compound presented by formula (I), and using the compound prepared by formula (I).

EFFECT: invention provides activation of penetration of the compound of formula (I), as well as maintaining the pre-set concentration of the drug preparation, even if a periodicity of the composition administration is reduced.

14 cl, 7 tbl, 2 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.

EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.

13 cl, 3 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is the use of 3,5-seco-4-norcholestan-5-one oxim-3-ole, or one of its acceptable acid addition salts, or one of its esters, or one of its acceptable acid ester addition salts as an antioxidant. What is shown is that the compound possesses systemic activity per os; it does not absorb visible UV-lights and interact with common sun protection products; it is presented in the form of a crystalline powder and keeps well at room temperature for at least 12 months; it is colourless, tasteless and odour-free.

EFFECT: properties make the compound to be preferred in cosmetic and food fields, and as antioxidant preserving agent used in particular in cosmetic, food and pharmaceutical products.

9 cl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition for local application containing fusidic acid within the range of 1 wt % to 5 wt % and mometasone within the range of 0.05 wt % to 2 wt % and a pharmaceutically acceptable carrier to be applied in treating or preventing inflammatory dermatoses caused by a secondary bacterial infection in a patient.

EFFECT: invention provides effective elimination of secondary bacterial infections in dermatologic injuries.

11 cl, 8 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and represents a drug preparation for treating respiratory diseases for simultaneous, sequential or separate inhalation introduction containing crystalline monteleukast in the form of an acid and mometasone.

EFFECT: invention provides extended range of the combined drug preparations for treating respiratory diseases in the form of inhalation.

7 cl, 5 ex, 17 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel estratrien-triazoles of general formula (I), which are useful in therapy, especially in treating and/or preventing steroid hormone dependent disorders, preferably steroid hormone dependent diseases or disorders requiring the inhibition of 17β-hydroxysteroid dehydrogenase (17β-HSD) such as 17β-HSD type 1, type 2 or type 3 enzyme.

EFFECT: improved method.

21 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to homogenous pharmaceutical composition for treatment of inflammatory disorders, which contains mixture of steroid anti-inflammatory or anti-histamine active ingredient in pharmaceutically acceptable water carrier with liposome. As steroid anti-inflammatory ingredient used is budesonide or fluticasone or their pharmaceutically acceptable salt, and antihistamine preparation is represented by azelastine or its pharmaceutically acceptable salt, concentration of active ingredient in water carrier is, in fact, equal inside and outside liposomic structures and varies ±20% when concentration of active ingredient inside and outside liposomic structures is compared. Polar lipid is swellable in water and represents phospholipid or glycosphingolipid. Invention also relates to method of composition obtaining, which lies in joint mixing of polar lipid, water phase and said active ingredient and mixture homogenising. Invention also relates to method of treating inflammatory disorders, including introduction of claimed composition to individuum, suffering from or sensitive to said disorders.

EFFECT: invention ensures reduction of irritation, for instance, in case of nasal introduction of composition.

52 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds applicable for treating or relieving a neurodegenerative disorder. There are also described methods of treating or relieving said disorders with said method involving the introduction a compound according to the present invention or a composition containing said compound in a patient.

EFFECT: method may be applicable for treating or relieving eg Alzheimer's disease.

21 cl, 9 ex, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to substituted extratriene derivatives of general formula (values of radicals are given in the claim), useful in therapy, especially for treating and/or preventing steroid hormone-dependent disorders which require inhibition of 17β-hydroxysteroid dehydrogenase (17-HSD) enzyme type 1, type 2 and/or type 3, as well as salts thereof, pharmaceutical preparations containing said compounds, as well as methods of producing said compounds.

EFFECT: improved method.

41 cl, 98 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a composition for preventing or treating peripheral neuropathy. The pharmaceutical composition for preventing or treating peripheral neuropathy containing a therapeutically effective amount of a compound presented by formula 1, or its salt and a pharmaceutically acceptable carrier: [Formula 1]

wherein R is a hydrogen atom, alkyl group C1-C4 or saccharide. A food composition for preventing or treating peripheral neuropathy containing the compound presented by formula 1, or its salt as an active ingredient.

EFFECT: compositions described above for preventing or treating peripheral neuropathy.

6 cl, 9 dwg, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: as a first active agent a pharmaceutical composition contains drospirenone in the amount equal to a daily dose when administering the composition and making 2 to 4 mg, and as a second active agent - ethinylestradiol in the amount equal to a daily dose and making 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives. Drospirenone as a part of the pharmaceutical composition has a particle surface area more than 10000 cm2/g. Preferentially, drospirenone is fine-grained or sprayed from a drospirenone solution by inert carrier particles. The preparation contains a number of separately packed and individually taken daily dosage units in a single package used for oral administration for at least 21 days running with said daily dosage units containing a combination of drospirenone and ethinylestradiol. The preparation may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: combination of drospirenone and ethinylestradiol provides reliable contraceptive activity ensured by the use of a maximum dose of drospirenone which causes no side effects, particularly, excess diuresis.

29 cl, 5 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to the substituted 4-benzylaminoquinolines and their heteroanalogs of the general formula (I): P-L-G (I) wherein G means compound of the formula: G(I) wherein K means -OR(7), -NH-CH2-CH2-SO3H, -NH-CH2-CO2H wherein R(7) means hydrogen atom, CH3; R1-R6 mean independently of one another hydrogen atom, -OR(10), -R(10) being one of residues R1-R6 means a bond with L always; R(10) means hydrogen atom, (C1-C4)-alkyl; L means (C1-C15)-alkyl being one or some structural CH2-fragments can be replaced for -C≡C-, -NR(11)-, -CO-, -O- wherein R(11) means hydrogen atom; P means: or wherein A means nitrogen atom (N); B means CH; D means CH; E means CH; R16-R24 mean independently of one another hydrogen atom, F, Cl atoms, (C1-C4)-alkyl being alkyl residues can be mono- or multiple-substituted with fluorine atom, NR(25)R(26), OR(25), COR(25), COOR(25), CONR(25)R(26) being one of residues R16-R(24) means a bond with L always; R25 and R26 mean independently of one another hydrogen atom, (C1-C4)-alkyl or benzyl. Also, invention relates to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and to a drug based on thereof for prophylaxis of supersaturation of bile with cholesterol. Invention provides preparing new compounds and a drug based on thereof that can be used for prophylaxis and treatment of patients suffering with gallstones.

EFFECT: improved preparing method, valuable medicinal properties of compounds and drugs.

10 cl, 32 ex

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