Systems of film coating for preparations with immediate release, creating enhanced anti-moisture barrier, and substrates with such coating

FIELD: chemistry.

SUBSTANCE: claimed invention relates to systems of a film coating for preparations with an immediate release for application on peroral dosed forms, such as pressed tablets and other perorally administered substrates, which possess an improved barrier protection means against moisture. The film coating composition contains 28-5 wt % of polyvinyl alcohol, 1-8 wt % of a polymer with pH-dependent solubility and, optionally, a plasticiser, a lubricant, an anti-adhesion substance, an alkalising substance and a pigment. Preferably, the polymer with pH-dependent solubility represents a copolymer of methacrylic acid and polyvinylacetophthalate (PVAP). Also described are compositions of the film coating, containing water suspension of powder mixtures, methods of applying the coatings on substrates and the substrates with the coating.

EFFECT: invention provides fast disintegration of the compositions in a medium with different pH (less than 30 minutes) and satisfactory characteristics of the anti-moisture barrier.

18 cl, 1 tbl, 27 ex

 

Cross-reference to related application

This application claims the priority under article 35 U.S.C. 119(e) patent application U.S. ser. No. 61/177380 registered on 12 may 2009, the contents of which are incorporated here by reference.

The scope of the invention

This invention relates to a film coating for drug immediate-release, having barrier properties against moisture. This invention relates also to pharmaceutical substrates having a film coating, and methods for their manufacture.

Description of the prior art

For several years, considerable effort has been expended to increase retention dosage forms. The drug cores of this product can be improved to contribute to ensure that the active ingredient was stable and compatible with other ingredients, or the coating can be applied to help protect the active substance from degradation associated with the access of moisture or oxygen in the local environment. When the drug cores are defined, a typical approach is the use of a film coating, which acts as a barrier that helps to protect the dosage form from their immediate environment, thereby improving the stability of dosage forms and increasing the shelf life of the product is the same.

In the US 5885617 described film coating based on polyvinyl alcohol (PVA) and soy lecithin, which provide excellent barrier properties against moisture.

In the US 6448323 described film coating containing polyvinyl alcohol, talc and the plasticizer (polyethylene glycol or glycerol), which has a very good, but higher degrees of transmission of water vapor than the composition of the '617, but mainly, in some applications, we need a much higher maximum speed of the fluid.

In the US 6420473 described film coating containing acrylic resin, an alkylating agent and a cure adhesive film coating. These compositions are not dissolved in simulated gastric juice (or 0.1 N HCl), even under stressful conditions over a period of one hour.

In KR patent 10-0758592 described dry composition of film coating containing 15-60 wt.% polyvinyl alcohol and 20-50 wt.% Intercollege polymer. This paper argues that, when the number Intercollege polymer is less than 20 wt.%, compositions exhibit degraded performance barrier from moisture.

There is still a need to develop a film coating for drug immediate-release, which simultaneously possess excellent barrier properties and give the highest possible is the speed of the fluid, as such compositions would represent the best performance and most cost-effective modes of application.

Summary of the invention

One of the features of the invention consists in receiving formulation a film coating for drug immediate-release, which has barrier properties against moisture, which, alongside compositions, i.e. essentially like compositions of the '617, at the same time significantly improve the maximum velocity of the fluid as compared with the compositions of the '617. An additional object of this invention to provide oral accepted dosage forms coated with the compositions of the present invention, which completely break down in environments with different pH (between pH of 1.2 and 6.8) through less than about 30 minutes.

In one aspect of the present invention presents a dry powder mixture, applicable to obtain compositions a film coating for drug immediate-release for the pharmaceutical and related areas. The powder mixture or composition comprises a combination of polymers, plasticizers, anti-stickiness, substances which improve the sliding and pigments. In preferred aspects of the present invention provides for the combination of polymers in which one polymer yavlyaetsyaprostota alcohol, and the other is a polymer that possesses dependent on the pH of the dissolution behavior.

In another aspect of the present invention presents a film coating composition containing a suspension of one or more of the powder mixtures described above. These suspensions preferably contain from about 10 to about 25% solids (not water). Yet another additional aspects include methods of coating oral accept substrates using a slurry coating, and the substrate with a coating produced according to these methods.

In the presented invention realized the advantages and improvements compared to previous prototypes. For example, the specialist can now obtain film-coated orally taken products with the property of immediate release and excellent barrier properties against moisture with maximum velocities of the fluid, significantly higher than the rate for drugs previous prototypes, with the lowest rate of water transmission (i.e. compositions '617). Thus, it is possible to obtain a coating with excellent protection against moisture and high maximum speed of the fluid.

It has been unexpectedly discovered that the addition of the drug with the polyvinyl alcohol polymer is dependent on the pH process is a cost can improve the barrier properties of film coatings from moisture without losing the characteristics of the immediate release into the environment with changing pH. In one of the embodiments of the present invention enable a polymer is dependent on pH solubility at a relatively low level, preferably between 1 and 15%, more preferably between 2 and 10%, and even more preferably between 4 and 8%, as found, gives the performance of the coating with the immediate-release with increased protection from moisture taken oral food substrates. Barrier protection is important for many types of oral accept food substrates, which are unstable in the presence of moisture. In light of the above-mentioned patent KR 10-0758592, which shows that the levels Intercollege polymer below 20% lead to the worst of barrier protection from moisture, was unexpectedly and surprisingly, that the addition of small amounts Intercollege polymer, i.e. about 1-15%, in the composition of film coating causes a significant improvement in barrier properties against moisture with respect to the properties associated with the product described in the aforementioned patent '323.

In preferred aspects of the present invention presents a film coating for drug immediate-release, giving a transmission rate of water vapor (SPIT; WVTR, also known as the rate of transmission of moisture vapour - SPVS; MVTR) of less than about 9 g of N2O/day/100 square inches, and a maximum speed of p is giving liquid, at least about 20 g/min 15" fully perforated boiler. This combination of properties for film coating system for medicines immediate-release is a clear advantage compared to existing marketed products.

Detailed description of the invention

For the purposes of this invention "is taken orally substrate" should be understood as meaning any pharmaceutically acceptable dosage form such as tablet, capsule, caplet etc. or any other veterinary or pastry product, which can be used by oral administration. The substrate can include one or more of the active pharmaceutical ingredients (API; API), food additives, etc.

For the purposes of this invention "dry powder" should be understood as including powders, which are relatively dry to touch, and not powders, which essentially does not contain moisture.

For the purposes of this invention "room temperature" should be understood as meaning a temperature usually in the range of from about 20°C (68°F) up to about 30°C (86°F)+/-3°C.

The first aspect of the present invention includes a powder mixture, which is applicable to obtain a film coating for drug with immediate selection. Data film coatings have excellent barriers is related properties against moisture and are usually plotted in the form of aqueous suspensions for oral accepted substrates, such as compressed tablets and the like, using the drageeing boiler or spraying techniques known to experts in this field. Powder mixtures of the present invention preferably include polyvinyl alcohol, polymer with a-dependent pH solubility, the plasticizer improves the sliding of the substance and, optionally, additional additives, including alkalizers substances, substances against stickiness and pigments.

In most embodiments the total amount of polymer (PVA + polymer dependent on pH solubility)included in the powder mixture of the presented invention is from about 30 to about 70% by weight. In some preferred embodiments, it ranges from about 30 to about 60%, and more preferably ranges from about 32 to about 55%.

Brands of polyvinyl alcohol, which, as found applicable for this invention are those that contain partially hydrolyzed polyvinyl acetate having a percent hydrolysis more about 86,5 mol %, and preferably in the range of from about 86,5 to 89 mol %. Preferably, polyvinyl alcohol micronizer to an average particle size of about 200 microns or less, in order to facilitate dissolution in water with formation of water covering solution. Preferably, polyvinyl who Peart could be dissolved in water at room temperature. The preferred interval for PVA in the compositions of the present invention is approximately 28-55% by weight on a dry film coating composition. In an alternative preferred embodiment, the amount of PVA in the compositions of the present invention is approximately 30-40% by weight on a dry film coating composition. The polymer is dependent on pH solubility is a polymer that can be dissolved when one biologically significant pH (e.g. pH=6,8), but not in another (for example, pH=1,2). A non-limiting list of suitable polymers is dependent on pH solubility include, for example, those which are soluble in normally present in the intestine interval of about 4-7, such as copolymers of methacrylic acid, comprising: a poly(methacrylic acid, methyl methacrylate) 1:1 sold, for example, under the trade name Eudragit L100; poly(methacrylic acid, ethyl acrylate) 1:1 sold, for example, under the trade names Eudragit L30D, Kollicoat MAE 30 DP and Eudragit L100-55; partially neutralized poly(methacrylic acid, ethyl acrylate) 1:1 sold for example, under the trade name Kollicoat MAE 100P; and poly(methacrylic acid, methyl methacrylate) 1:2 sold, for example, under the trade name Eudragit S. Additional polymers, which are essentially insoluble at low pH (e.g., about 1.2) and soluble at high pH (in the example, approximately 5), as well as those which it is found applicable, are polyvinylacetate (PVAP), PVF, processed together with titanium dioxide (PVAP-T), acetotartrate (AFC; CAP), acetosella hydroxypropylmethylcellulose (AU-GPMC) and phthalate of hydroxypropylmethylcellulose (f-GPMC).

Other applicable polymers are polymers that are essentially insoluble at pH above about 5 but soluble at a lower pH. These polymers are usually called reverse intersolubility polymers. One particularly suitable reversible intersolubility polymer is poly(butylmethacrylate, 2-dimethylaminoethylmethacrylate, methyl methacrylate) 1:2:1. sold, for example, under the trade name Eudragit E.

You can use combinations of the previously mentioned pH-dependent polymers, as well as a fully formed system containing one or more of the polymers. Fully formed film coating containing polymers c are dependent on pH solubility include trademarks Acryl-EZE (containing Eudragit L100-55), Sureteric (containing PVF) and Chromateric (containing Kollicoat MAE 100P). Polymers or formed coatings containing them, dependent on pH solubility, can be used so that the pH-dependent polymers are present at a level 1-15%, preferably between 2 and 10%, and more predpochtitel is about, between 4 and 8% of the final dry film coating composition.

The plasticizer is preferably a polyethylene glycol (PEG) or triethylcitrate (CHP). Preferred brands of PEG are those that exist in the solid state at room temperature, including brand with a molecular weight of from about 3000 to 8000 g/mol.

Improves slip substance is preferably talc. Improves slip substance is usually used in order to facilitate the movement of the tablets in the flow over each other and thus create a fine finish, smooth surface. The number present improves the sliding of the substance will depend on the needs, but may broadly range from about 9 to about 50% by weight, preferably in the range from about 12 to about 40%, and more preferably, from about 15 to about 30%.

Alkalizing substance may be sodium bicarbonate or other components such as other known bicarbonate, carbonate, phosphate or hydroxide of sodium or of potassium, magnesium carbonate, magnesium hydroxide, ammonium carbonate, ammonium bicarbonate, calcium hydroxide or mixtures thereof, which can neutralize the acid groups on the main chain of the polymer is dependent on pH solubility. Salts of sodium or potassium are preferred by not is which aspects of the present invention. Sodium bicarbonate is the preferred alkalizing agent. Alkalizing substance used mainly to maintain complete solubility of the drug and to ensure that it is not necessary to pass through a sieve of a solution/suspension film coating before use. The amount of alkalizing substances, if enabled, will depend on the needs and is based on the degree necessary to neutralize the drug. With a wide range this is a number between about 1 and about 6% by weight from the level of the acrylic polymer is dependent on pH solubility in the product. Preferably the interval is from about 2 to about 4% by weight from the level of the acrylic polymer is dependent on pH solubility in the product, and more preferably, from about 2 to about 3% by weight from the level of the acrylic polymer is dependent on pH solubility in the product. In cases where the polymer is PVAF or PVAP-T, the amount of alkalizing substance is from about 8 to about 20%, preferably from about 10 to about 14%. In another alternative embodiment of unrelated alkalizing substance is eliminated by using a partially neutralized brand pH-dependent polymer. Partially neutralized poly(methacrylic acid, these shall acrylate) 1:1, sold under the trade name Kollicoat MAE 100P, is one of these brands. However, in some other aspects of the present invention alkalizing substance can be excluded, in General, without side effects.

Substance from the stickiness can be selected from lecithins, stearic acid, Polysorbate, glycerylmonostearate, poloxamers, fume silica, bentonite, edible hydrogenated vegetable oils, monoglycerides, diglycerides, different types of wax and mixtures thereof. Substance from the stickiness is primarily used to reduce sticking of the tablet to tablet that can occur during film coating for pharmaceutical tablets and the like when using aqueous suspensions/dispersions on the basis of the compositions of the present invention. The total number of substances present from the stickiness will depend on the needs, but may vary within wide limits from about 4 to about 25% by weight. Preferably this range is from about 6 to about 14%, and preferably from about 8 to about 12%.

The pigments can be any approved for use in pharmacy and food industry dyes, cloud emulsions or paints. For example, the pigments may be aluminum lacquer, iron oxides, titanium dioxide, natural coloring and or pearlescent pigments (for example, pigments based on mica, sold under the trade name Candurin). Examples of such pigments are listed in US 4543570, which is included here by reference. These pigments can be used in powder mixtures in the range (by weight) from about 1 to about 40% pigment, preferably from about 4 to about 32%, and more preferably, from about 7 to about 30%. It will be understood, however, that the amount of pigment in powder mixtures of this invention are represented by the amount that is sufficient or effective to impart the desired form of the outer coating on the surface of the substrate, which must be covered.

In addition, the powder mixture may also include additional or auxiliary ingredients, usually found in film coatings. A non-limiting list of such excipients include surfactants, excipients to obtain a suspension, sweeteners to improve the taste and smell substances, etc. and mixtures thereof. The preferred surfactant is sodium lauryl sulfate.

One of the defining moments for the presented invention is the ability to give the surface an improved barrier properties against moisture consumed products. In this respect, the components of the powder mixtures must meet all approved state is artenum requirements for human consumption.

Powder mixture receiving, using standard methods of blending or mixing of dry substances, known to specialists in this field. For example, the ingredients are weighed separately, add in the appropriate apparatus and mixed for a sufficient time to obtain essentially homogeneous mixture of ingredients. The time required to achieve such real uniformity is, of course, depend on the lot size and the used apparatus. If any of the ingredients of powder preparation are liquids, they are added only after all of the dry ingredients were sufficiently mixed, and the combination of wet and dry ingredients mixed for an additional amount of time to ensure homogeneity, when all the liquid has already been entered.

As mentioned above, the batch size will be changed as needed. A non-limiting list of suitable devices for mixing includes diffusion mixers, such as perekrestnotochny V-mixer or serdechnikov mixer available for purchase at Patterson-Kelly, or you can use convection mixers, such as mixers, Ruberg, or CVM, available at Azo and Readco, respectively. Mixing the above-mentioned preparations can also be achieved by processing the ingredients in granular form with the item is a receiving composition indelible granular coating methods, including, but without limiting it, getting wet mass granulation in the fluidized bed, spray granulation and dry pressing, roll compaction or clumping. Other methods of mixing will be obvious to experts in this field.

For purposes of illustration, and without limitation, this aqueous suspension containing about 20% solids, can be obtained by dispersion 80,0 grams of the mixed powder mixtures described herein above, in 320,0 grams of water at room temperature. Water is weighed into a suitable vessel, i.e. a vessel with a diameter approximately equal to the depth of the final suspension. Mixer with low shear, preferably a mixer having a blade diameter of approximately one-third the diameter of the vessel for mixing, lowered into the water and rotate to create a funnel from the edge of the vessel down to about just above the mixing blade to prevent trapping air. Add 80 g of dry composition for film coating in the hopper by the speed at which there is no accumulation of dry powder. The speed and depth of the mixing blades pick up to avoid pulling air into the slurry so as to avoid foaming. The suspension is stirred at low speed, preferably, 350 rpm or less for a time sufficient to provide the treatment, what becomes a homogeneous mixture. When using the above download size as a guide, it is important for a 45-minute mixing time. Then the suspension is ready for spraying in the pharmaceutical substrates, and the like. Specialists in this field will understand that there are many ways to get essentially homogeneous mixture of solid substances in water and that the scope of the present invention in no way depends on the used hardware.

In further additional embodiments of the present invention presents taken oral substrates having enhanced barrier against moisture and high maximum feed rate of the liquid for film coating with immediate-release, as well as methods of coating taken oral substrates with the use described here suspensions. As will be described in the examples below, these methods include the application of compositions (suspensions) film coating with enhanced barrier property against moisture and high maximum speed of the fluid for drugs with immediate selection on the oral surface of the received substrate. Film coating may be applied as part of the coatings applied in the drageeing boiler, or process sprayed coating that is typically used to cover such product is. The amount of the coating will depend on several factors, including the substrate, which must be covered, and the apparatus used for coating, etc. In most aspects of this invention, however, the substrates will be covered up to a theoretical weight gain from about 0.25 to about 5.0 percent. Preferably, theoretical weight gain is from about 0.5 to about 4.0%, and more preferably, when theoretical weight gain is from about 1.0 to about 3.0 percent by weight of the substrate.

As mentioned above, solutions for the coating of the present invention may also include ancillary ingredients in addition to the powder mixture and water.

Covered accept oral substrates described above can be manufactured that include podogrevayushchie film coating between the received oral substrate and a film coating with enhanced barrier properties. Selected podporuje preferably is based composition of edible film coating that is compatible and linked as taken orally substrate and coated with enhanced barrier properties. Thus, the person skilled in the art can choose from a wide variety of pharmaceutical or acceptable for food poritids use as photocrati according to this invention, such as products brand name Opadry®, available for purchase from use Inc., or other containing freely soluble cellulose polymers or polymers PVA according to this invention. Podporuje also applied to the substrate to obtain from about 0.25 to about 5.0% of body weight taken orally substrate.

No matter which method or specific substances included in the composition of film coating, taken orally substrates presents invention preferably have a penetration rate of water vapor less than 9, and preferably less than about 6 g/water/day/100 square inches and, thus, minimizes the hydrolytic destruction of the moisture sensitive API.

A non-limiting list of suitable substrates that can be coated with the coating system of the present invention, includes pressed tablets, caplet, kernel, including pharmaceuticals, nutraceuticals and food delivery, and any other generally recognized in the field of oral accept kernel.

EXAMPLES

The following examples serve to further understanding of this invention, but do not mean in any way limit the effective scope of this invention. All the ingredients are in weight %.

EXAMPLE 1

Preferred n is apparatom dry composition for coating of the present invention is the following:

ComponentPercentageGrams
Polyvinyl alcohol (PVA)35,0028,00
Poly(methacrylic acid,
The acrylate) 1:1
(Eudragit L100-55)4,003,20
Talc23,8819,10
PEG 335012,009,60
Titanium dioxide20,0016,00
Blue #2 lacquer5,004,00
Sodium bicarbonate0,120,09
100,0080,00

The manufacture of the drug

The film coating suspension was obtained by otoshiana all ingredients in the plant for food production is DSTV/mixer suitable size and mixing for 5 minutes to obtain a homogeneous mixture. All ingredients of this drug are dry powders, but in the examples that follow, if any of the ingredients of the product are liquids, they were added to the dry mixture after the initial 5 minutes of mixing, and the total mixture was stirred for an additional 5 minutes after all the liquid had entered.

Hydration of the drug

Eighty grams of the mixed mixture was dispersible in 320 grams of water at room temperature to obtain an aqueous suspension of coatings containing 20 wt.% solid substances. Water was weighed in a vessel with a diameter approximately equal to the depth of the final dispersion. Mixer with low shear immersed in the water and the rotation was established to create a funnel from the edge of the vessel down to a depth immediately above the mixing blade to prevent trapping air. In the funnel was added 80 grams of dry film coating composition at a rate at which there was growing excess dry powder. The speed and depth of mixing vanes were installed to avoid pulling air into the slurry so as to avoid foaming. The suspension was stirred at low speed, preferably 350 rpm or less, for 45 minutes, and then it is ready for deposition on substrates, such pharmaceutical tablets, and the like.

p> The coating on the drug

For a batch size of 1.5 kg 10 mm standard convex tablets placebo was coated with the above slurry in the boiler O'hara LabCoat II, equipped with a fully perforated insert for coating with a lateral loading, with a diameter of 15", and nozzle 1-Spraying Systems Schlick (model 931, equipped with a nozzle 1.2 mm). Average coverage settings were: inlet temperature (Th) 65°C, outlet temperature (of Twig) 48°C, the temperature in the layer (TC) 45°C, the air flow of 250 cubic meters/HR air pressure-0.1 inches of water, the velocity of the fluid (ALE) 15 g/min, spraying air pressure (PD) 1.5 bar, the rotation speed of the boiler (SC) 22 rpm For tablets used theoretical weight gain during coating, equal to 3.0%, and the coated tablets were smooth, non-sticky and glossy.

Determine the maximum velocity of the fluid (MSPI)

The maximum speed of the fluid was determined using a 1.5 kg batch size of 10 mm standard convex placebo, which were covered with a coating according to the description of the present invention in the boiler O'hara LabCoat II, equipped with a fully perforated insert for coating with a lateral loading, with a diameter of 15", and nozzle 1-Spraying Systems Schlick (model 931, equipped with a nozzle 1.2 mm). Average parameters cover the Oia were: inlet temperature (Th) 65°C, outlet temperature (of Twig) 48°C, the temperature of the layer of coating (TC) 45°C, the air flow of 250 cubic meters/HR air pressure-0.1 inches of water, pressure spraying air (DR) 1.5 bar, the rotation speed of the boiler (SC) 22 rpm feed Rate of the liquid (ALE) was gradually increased until, when there was a complete sticking with rotation to the surface of the boiler. At this point, the spraying speed was reduced to obtain the flow rate at which the tablets are not sticking to the boiler, and that the spraying speed was recorded as the maximum flow rate. The maximum speed of the fluid to example 1 was defined as equal to 21 g/min

The transmission rate of water vapor (SPIT; WVTR)

Data on the rate of transmission of water vapor (SPIT), also known as the rate of transmission of moisture vapour (SPFI; MVTR), was obtained by making a sample formed of a film of the dispersion on a flat surface, and then drying in a laboratory thermostat at 40°C. the Aim was to obtain a film of 100 μm thickness (0.1 mm) for further testing. The drying time varied depending on the composition of the preparation and the content of solids in the dispersion. If not present visible defects, used a digital micrometer to confirm that the average film thickness is in the range of the t 90 to 110 microns. Installation VTI WPA-100 was configured at the initial phase of drying, when the sample was purged at 25°C and 100 cm3/min (dry N2) for 15 minutes, and then one side of the sample was rinsed with a stream of nitrogen at 25°C./80% RH at a speed of 200 cm3/min to determine the stable rate of water transmission through the sample. The transmission rate of water vapor to example 1 was installed in 4.8 g of water/day/100 square inches.

Test raspadaemost

Test raspadaemost performed in accordance with the method of determining raspadaemosti USP. Six tablets were obtained as previously described, and placed in the set wicker containers and placed or treated water, or in simulated gastric juice (0,1N HCl) for up to one hour. Capacity moved up and down at a rate of approximately 28-32 cycle/minute. The integrity of the tablets were evaluated during the test period and noted the time of the collapse of the first and last tablet. These values are then used to determine the average decay time for the samples in each environment. Average time decay for nuclei placebo, covered with a 3% increase in weight from example 1 in purified water, as found, is 9 minutes 31 seconds, while this assessment in 0.1 N HCl was 9 minutes 9 seconds. This confirms that the film coating of the present invention is suitable for use as on the of rite for preparations immediate-release.

EXAMPLES 2-23

Received additional drugs were dispersible in water and covered their tablets as described in example 1. Relevant coated tablets were then tested by the same methods described in example 1.

Example2
Component%
Polyvinyl alcohol : 35,00
Eudragit L100-554,00
Triethylcitrate12,00
Sodium bicarbonate0,12
Talc23,88
Titanium dioxide20,00
Blue #2 lacquer5,00
Max. spraying speed (R/min)
15 insert
20
SPIT (g H2O/day/100 inch2)7,6
The average disintegration time in purified water is (min:sec) 06:58
The average time of dissolution in 0.1 N HCl (min:sec)06:49

Example3456789 (control)
Components%%%%%%%
Polyvinyl alcohol : 38,0537,0736,1035,1233,1731,220,00
Eudragit L100-550,981,952,933,905,857,8038,61
PEG 800012,00 11,9911,98of $ 11.9711,9511,9311,85
Sodium bicarbonate0,030,060,090,120,180,231,16
Talc24,0023,9823,9623,9423,9023,8623,70
Titanium dioxide19,9619,9619,9619,9619,9619,9619,75
Blue #2 lacquer4,994,994,994,994,994,994,94
Max. spraying speed (R/min)
15 insert
20202217151620
SPIT (g H2O/day/100 inch2)the 5.76,15,53,23,13,4the 5.7
Average time decay in treated
water (min:sec)
04:1805:0404:1104:3004:1204:3304:57
The average disintegration time in
of 0.1 N HCl (min:sec)
04:3305:4004:0504:2005:1003:54>60:00

Por what measures 10111213141516
(control)
Components%%%%%%%
Polyvinyl alcohol : 38,0537,0736,1035,1233,1731,220,00
Partially neutralized
Poly(methacrylic acid, tilatequila) 1:1
(Kollicoat MAE 100P)
0,981,952,933,905,857,8038,61
PEG 800012,0011,9911,98of $ 11.9711,9511,93 11,85
Sodium bicarbonate0,030,060,090,120,180,231,16
Talc24,0023,9823,9623,9423,9023,8623,70
Titanium dioxide19,9619,9619,9619,9619,9619,9619,75
Blue #2 lacquer4,994,994,994,994,994,994,94
Max. the velocity of the spray is s (g/min)
15 insert
23201818171726
SPIT (g H2O/day/100 inch2)the 5.7a 3.95,9a 3.93,43,53,2
The average disintegration time in purified water (min:sec)04:2004:3504:3405:0504:1504:3304:21
The average time of dissolution in 0.1 N HCl (min:sec)04:1904:4504:2104:2304:0604:25>60:00

Example17181920
Components%%%%
Polyvinyl alcohol : 35,1235,1235,1234,77
Eudragit L100-553,903,903,903,86
PEG 335012,0012,0012,0011,88
Sodium bicarbonate0,000,121,002,00
Talc23,9823,8622.98mm22,75
Titanium dioxide20,0020,0020,0019,80
Blue #2 lacquer is 5,005,005,004,95
Max. spraying speed (R/min)
15 insert
22212324
SPIT (g H2O/day/100 inch2)of 5.89of 5.8911,6713,93
The average disintegration time in purified water (min:sec)08:2508:0709:3208:26
The average time of dissolution in 0.1 N HCl (min:sec)08:1708:0609:3107:11

Example212223
Components% %%
Polyvinyl alcohol : 30,630,630,6
Eudragit L100-553,43,43,4
PEG 335061218
Glycerylmonostearate2,52,52,5
Sodium bicarbonate0,120,120,12
Talc32,3826,3820,38
Titanium dioxide202020
Blue #2 lacquer555
Max. spraying speed (R/min) 15 insert192429
SPIT (g H2O/day/100 inch2)5,625,487,18
The average disintegration time in purified water (min:sec)09:3609:2709:15
The average time of dissolution in 0.1 N HCl (min:sec)09:2208:3509:31

Example24
Component%
Polyvinyl alcohol : 35,12
PVAF3,90
PEG 335012,00
Sodium bicarbonate0,12
Talc32,38
Titanium dioxide20,00
Blue #2 lacquer 5,00
Max. spraying speed (R/min)
15 insert
29
SPIT (g H2O/day/100 inch2)7,1
The average disintegration time in purified water (min:sec)08:22
The average time of dissolution in 0.1 N HCl (min:sec)08:45

EXAMPLE 25

Products and procedure of example 1 is repeated, except that acetosella hydroxypropylmethylcellulose (AU-HPMC) used to replace the poly(methacrylic acid, ethyl acrylate) 1:1.

EXAMPLE 26

Products and procedure of example 1 is repeated, except that the phthalate of hydroxypropylmethylcellulose (f-HPMC) used to replace the poly(methacrylic acid, ethyl acrylate) 1:1.

EXAMPLE 27

Products and procedure of example 1 is repeated, except that poly(butylmethacrylate, 2-dimethylaminoethylmethacrylate, methyl methacrylate 1:2:1 (Eudragit E PO) used to replace the poly(methacrylic acid, ethyl acrylate) 1:1.

Unexpectedly observed that the minimum addition of a polymer is dependent on pH solubility can get excellent performance bar is hernych properties against moisture and high maximum speed of the fluid without loss of properties raspadaemosti in water or acidic environment. In addition, it was found that the use of a polymer is dependent on pH solubility level between 4 and 8 wt.% gives the greatest advantage in relation to excellent barrier properties and minimal impact on the properties of raspadaemosti or the cost of the drug. This is a surprising result, as it was assumed that a large part of the polymer is dependent on pH solubility would be required to achieve the enhanced barrier properties of the film coating against humidity and that at this higher level it has the potential to lead to increased time raspadaemosti for tablets in an environment with a low pH.

It is noteworthy that the estimated preparations coating with a polymer dependent on pH solubility level include more than 38%, such as in examples 9 and 16, engraved on the tablets with a 3% weight gain was not dissolved in the acidic environment after 1 hour and did not enhance performance barrier properties against moisture compared with the figures of film coating, obtained by incorporating a polymer is dependent on pH solubility in the 4-8 wt.%.

If additional unexpected result was observed, although the level of alkalizing substances used in drug had no effect on the maximum speed of the fluid or raspadaemost tablets PLA is ABO in water or acidic environment, he had a significant impact on the barrier properties of the film coating and the lower the level of alkalizing substances, the better the barrier properties of the film coating. However, when the amount of alkalizing substances than are described here, i.e. about 6% or below, you can see that any advantage gained by incorporating polymers, pH-dependent, progressive lost.

It was found that when at the same time using different levels of plasticizer (polyethylene glycol or triethylcitrate) improves the slip substance (talc) and the remedy of stickiness (glycerylmonostearate), the maximum speed of the fluid increases with minimum impact on the barrier properties or speed raspadaemosti.

In addition, it was observed that when using polivinilatsetatftalat as a polymer dependent on pH solubility, see example 24, the properties SPIT this drug is lower than the properties associated with the products corresponding to U.S. patent No. 6448323, with no impact on raspadaemost in an acidic environment. It is noted that the maximum rate of fluid supply to the resulting system is excellent and comparable with the figure of the preparation described in patent '323,

Comparison with prior art

To the floor is the bottom of the confirmation that enhanced barrier properties and the maximum speed of the fluid for drugs of this invention, this description surpass prototypes and preferable to them, there were a series of evaluations of prototypes and these drugs film coating. These estimates and their methods are described in detail below.

Comparative examples

To compare performance of the above tables for the compositions of this description in relation to other systems film coatings, are well known in this field, we have received the following comparison examples, film-coated and tested. Estimate the maximum velocity of the fluid and barrier properties against moisture is installed, as described below.

Comparative example: System Opadry® AMB from US 5885617

System-based Opadry® AMB, product use, hydrational and covered with a film of O'hara LabCoat II, equipped with a 15" box, using the same substrates and conditions, which are described in example 1. The maximum speed of the fluid for this drug, as defined, equal to 11 g/min, and the rate of water vapor transmission film of 6.4 g of N2O/day/100 square inches. In patent '617 described that the maximum speed of the liquid supply system Opadry® AMB 25-30 g/min 24" boiler and its barrier properties about 6 g of N2O/day/100 kVA is Ratna inches. These results are comparable with the data on this description, provided that differences in the scale of the coating process. As can be seen from the summarizing table below, the preparations of the present invention provide essentially the same barrier properties and properties raspadaemosti in the products described in patent '617, but provide the desired improvement in their significantly improved the performance speed of the fluid.

Comparative example: System Opadry® II from US 6448323

System-based Opadry® II, product use, hydrational and covered with a film of O'hara LabCoat II, equipped with a 15" box, using the same substrates and conditions, which are described in example 1. The maximum speed of the fluid for this drug, as defined, equal to 29 g/min, and the rate of transmission of water vapor for film 13.5 g H2O/day/100 square inches. In patent '323 described that the maximum speed of the liquid supply system Opadry® II is equal to 60 g/min in a 24" pot, and its rate of transmission of water vapor is approximately 10 g of N2O/day/100 square inches. Again, these results are comparable with the data on this description, provided that differences in the scale of the coating process.

Comparative example: System Acryl-EZE® from US 6420473

System on the basis of Acryl-EZE®, available for purchase from use, was hydrational and applied and film coating in O'hara LabCoat II, equipped with 15" box, using the same substrates and conditions, which are described in example 1, except that the temperature of the layer must be reduced by maintaining at 35°C and the air volume was increased to 350 cubic meters/hour. The maximum speed of the fluid for this drug, as defined, is 25 g/min and the rate of transmission of water vapor and 1.5 g of N2O/day/100 square inches. It is established that the preparation of this coating is not soluble in 0.1 N acid solution in the standard test conditions for raspadaemost.

td align="center"> 04:35
Pivot table
ExampleSPIT
(Mr2About/
day/100
inch2)
Max. the feed speed
liquid (g/min)
15 insert
Average
raspadaemost in purified water
(min:sec)
Average raspadaemost in 0.1 N HCl
(min:sec)
14,82109:3109:09
27,62006:583the 5.72004:1804:33
46,12005:0405:40
55,52204:1104:05
63,21704:3004:20
73,11504:1205:10
83,41604:3303:54
9the 5.72004:57>60:00
10the 5.72304:2004:19
11a 3.92004:45
125,91804:3404:21
13a 3.91805:0504:23
143,41704:1504:06
153,51704:3304:25
163,22604:21>60:00
175,92208:2508:17
185,92108:0708:06
1911,72309:3209:31
20 2408:2607:11
215,61909:3609:22
225,52409:2708:35
237,22909:1509:31
247,12908:2208:45

Comparative examples
Opadry®
AMB
6,41108:0908:20
Opadry®
II
13,52905:5105:56
Acryl-EZE®1,52510:46>60:00

Although the description is believed, in the present embodiment of the present invention are preferred, assistants will understand that there may be changes and modifications without departing from the scope of its essence. Assume that declared all such changes and modifications that fall within the valid scope of this invention.

1. The composition of film coating with immediate-release formulation having enhanced barrier properties against moisture containing 28-55% by weight of polyvinyl alcohol, 1-8% by weight of a polymer is dependent on pH solubility selected from the group consisting of a copolymer of methacrylic acid, polivinilatsetatftalat (PVAP), PVF, revised in collaboration with titanium dioxide (PVAP-T), acatitla cellulose phthalate of hydroxypropylmethylcellulose, acetolactate hydroxypropylmethylcellulose, poly(butyl methacrylate, 2-dimethylaminoethylmethacrylate, methyl methacrylate) 1:2:1, and combinations thereof, and, optionally, a plasticizer or an agent for improving the sliding.

2. The composition according to claim 1, in which the polymer is dependent on pH solubility selected from the group consisting of a copolymer of methacrylic acid, polivinilatsetatftalat (PVAF).

3. The composition according to claim 1, in which the methacrylic acid copolymer is poly(methacrylic acid, methyl methacrylate) 1:1, in the example, such as Eudragit L100; poly(methacrylic acid, ethyl acrylate) 1:1, such as Eudragit L30D, Kollicoat MAE 30 DP and Eudragit L100-55; partially neutralized poly(methacrylic acid, ethyl acrylate) 1:1, such as Kollicoat MAE-100 ROUBLES; or poly(methacrylic acid, methyl methacrylate) 1:2, such as Eudragit S.

4. The composition according to claim 1, additionally containing one or more of alkalizing substances substances from stickiness and pigments.

5. The composition according to claim 1, wherein the plasticizer is polyethylene glycol and triethylcitrate.

6. The composition according to claim 1, and improves the sliding ingredient is talc.

7. The composition according to claim 1, and polyvinyl alcohol is 30-40% by weight of composition.

8. The composition according to claim 1, whereby the polymer is dependent on pH solubility is 4-8% by weight of composition.

9. The composition according to claim 1, and improves the slip substance is 9-50% by weight of composition.

10. The composition according to claim 1, additionally containing up to about 6% by weight of alkalizing substances, calculated on the basis of the number of polymer dependent on pH solubility.

11. The composition according to claim 1, additionally containing an amount of from about 2 to about 4% by weight of alkalizing substances, calculated on the basis of the number of polymer dependent on pH solubility.

12. The composition according to claim 1, further is part containing a number from about 2 to about 3% by weight of alkalizing substances, calculated based on the number of polymer dependent on pH solubility.

13. The aqueous suspension obtained by mixing the composition according to claim 1 with water.

14. Taken orally, the substrate is coated with a suspension according to item 13.

15. Taken orally, the substrate with the coating 14, and the coated substrate dissolves in water with a pH of 1.2 through in less than 30 minutes.

16. Pharmaceutically acceptable oral dosage form containing oral accept the substrate, the coated film by coating with barrier properties against moisture, and the specified film coating contains 28-55% by weight of polyvinyl alcohol, 1-8% by weight of a polymer is dependent on pH solubility selected from the group consisting of a copolymer of methacrylic acid, polivinilatsetatftalat (PVAP), PVF, revised in collaboration with titanium dioxide (PVAP-T), acatitla cellulose phthalate of hydroxypropylmethylcellulose, acetolactate hydroxypropylmethylcellulose, poly(butyl methacrylate, 2-dimethylaminoethylmethacrylate, methyl methacrylate) 1:2:1, and combinations thereof, and, optionally, a plasticizer and/or improving the slip substance.

17. Pharmaceutically acceptable oral dosage form according to item 16, and the film coating has a transmission rate of water vapor less than about 9 g of N2O/day/100 square inch is.

18. A method of obtaining a pharmaceutically acceptable oral solid dosage forms, comprising: coating for oral accepted the substrate with a film coating suspension according to item 13 at the maximum speed of the fluid, of at least 20 g/min 15" fully perforated boiler until then, as long as the substrate is covered with a sufficient amount of suspension specified film coating until, when on the specified substrate is formed by film coating, which has a transmission rate of water vapor less than about 9 g of N2O/day/100 square inches.



 

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9 cl, 55 dwg, 46 tbl, 3 ex

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EFFECT: lower toxic effect of the retina, improved intraoperative visualisation of cortical layers of the vitreous body.

3 ex

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