Pharmaceutical composition and a pharmaceutical preparation containing potassium, sodium or tris salt oxaprozin, their application to eliminate or reduce pain in a mammal for the treatment of inflammation and disorders associated with inflammation in a mammal, the method of obtaining pharmaceutical drug

 

(57) Abstract:

The invention relates to medicine and relates to pharmaceutical compositions for oral administration, which produces the desired therapeutic response, in tablets, drops or other molded form, which includes potassium, sodium or Tris salt oxaprozin, and tablet, caplet or other molded form of pharmaceutical compositions is usually dissolved by approximately 75% in environments phosphate buffer for about 30 minutes, the Composition may contain a suitable lubricating substance, a suitable binder. The pharmaceutical composition provides for eliminating or reducing the intensity of pain in a mammal and treatment of inflammation and associated with inflammatory disorders such as rheumatoid arthritis and osteoarthritis, and related disorders and conditions in a mammal. 5 C. and 31 C.p. f-crystals, 84 PL., 2 Il.

(1) the Area of technology

The invention relates in General to new pharmaceutical compositions or preparations containing salt oxaprozin for oral or other applications, and to methods of treatment using these drugs. These drugs contain only insignificant amounts and / or amount of binding - methylcellulose. These drugs dissolve more quickly and lead to a more rapid onset of action of the active agent is a salt oxaprozin than pharmaceutical preparations containing oxaprozin. Thus, these drugs are used for treatment of pain (as analgesic agents), as well as for the treatment of inflammation. In particular, this invention relates to pharmaceutical preparations containing potassium, sodium or Tris salt oxaprozin in combination with a pharmaceutically acceptable carrier, and methods for treating pain and inflammation using these compounds.

Oxaprozin is a non-steroidal anti-inflammatory drug (NSAID) class of propionic acid, chemically referred to as 4,5-diphenyl-2-oxazolepropionic acid, which is currently marketed in the United States by the pharmaceutical company G. D. Searle & Co., Skokie, Illinois, under the trademark DAYPRO. Chemical formula oxaprozin is:

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DAYPROtablets (capley (pill oval) for oral administration contain 600 mg oxaprozin as active funds and have the composition shown in table. 11.

In cases where it is important started fast 1200 to 1800 mg (not to exceed 26 mg/kg).

Potassium salt oxaprozin has a solubility of 370 mg/ml, Tris salt oxaprozin has a solubility 380 mg/ml and sodium salt oxaprozin has a solubility 260 mg/ml, in comparison with the solubility of 1.7 mg/ml oxaprozin. Thus, these salts oxaprozin rapidly dissolve and have a higher rate of absorption, resulting in faster onset of action and enhanced analgesic (pain) actions.

Previously believed that the same drug oxaprozin, which is currently marketed in the US by company G. D. Searle & Co. under the trademark DAYPROcan be used for potassium, sodium or Tris salt forms oxaprozin. However, it was found that the tablets obtained from this drug for potassium salt oxaprozin, deformed and do not break (not disintegrate in water and not dissolve in environments phosphate buffer, and as a result, in the first hour of these tablets is not released or is released a small number of active funds.

I believe that magnesium stearate (used as a lubricant in DAYPROcomposition) interacts with potassium in tablets containing kolstoe disintegration (disintegration and dissolution of tablets.

Subsequently it was found that the magnesium stearate used in the compositions of potassium, sodium or Tris salt oxaprozin, is not the only ingredient in these drugs, which has an adverse effect on raspadaemost and dissolution of tablets containing these compounds. Currently theoretically believe that disintegration (raspadaemost) and the dissolution of these tablets has a deleterious effect as a lubricating substance, magnesium stearate, and connecting - methylcellulose.

There is a need for the development of pharmaceutical preparations of the present invention, where approximately 75% of the active ingredient (potassium, sodium or Tris salt oxaprozin) dissolved in the medium phosphate buffer for about 30 minutes. The most preferred pharmaceutical preparation has a property (characteristic), which consists in the fact that nearly 100% of the potassium salt oxaprozin dissolve in the environment of phosphate buffer for 30 minutes. For comparison, when the modern DAYPROthe drug initially oxaprozin replaced by potassium salt oxaprozin, only about 23% of potassium salt oxaprozin dissolves in the environment of phosphate buffer for 30 Ministro, and potassium salt oxaprozin has a significantly higher solubility than oxaprozin, the compositions of tablets containing potassium salt oxaprozin have significantly more rapid onset of action of the active funds in comparison with DAYPRO. As a result, the composition of tablets containing potassium salt oxaprozin which are useful as analgesic for the treatment of pain, as well as anti-inflammatory drugs for the treatment of diseases, such as rheumatoid arthritis and osteoarthritis.

The invention

This invention provides a pharmaceutical preparation for oral administration, pharmaceutically acceptable and which provides the desired therapeutic response, in tablets, drops or other molded form, which includes potassium, sodium or Tris salt oxaprozin.

This invention also provides a pharmaceutical preparation for oral administration, which is pharmaceutically acceptable and which provides a therapeutic response in the tablet, drip or other molded form, which includes: (a) potassium, sodium or Tris salt oxaprozin as an active ingredient; and (b) Poupart for oral administration, which is pharmaceutically acceptable and which provides a therapeutic response in the form of tablets, capsules or other molded form, which includes: (a) potassium, sodium or Tris salt oxaprozin as an active ingredient; (b) suitable lubricating substance; and (C) a suitable binder.

This invention also provides a method of eliminating or reducing the intensity of pain in an animal and methods of treatment of inflammation and diseases associated with inflammation, such as rheumatoid arthritis and osteoarthritis, and related diseases and conditions in animals, including the introduction of the claimed pharmaceutical drug the animal.

The pharmaceutical preparations of this invention may contain small amounts of metallic stearates (less than 0,976% by weight of the total tablet or other molded forms containing such a composition, such as a lubricant, magnesium stearate, calcium and zinc, in order to prevent harmful effects on raspadaemost and/or dissolving tablets, drips or other extruded forms of these compounds. Preferably, the pharmaceutical preparations of the present invention do not contain any metallic stearates.

FA is ellulose (less than 2% by weight of the total tablet, containing such a composition), in order to prevent adverse influence on the disintegration and/or dissolution of tablets, drips or other extruded forms of these compounds. Preferably, the pharmaceutical preparations of the present invention do not contain methylcellulose.

A detailed description of the invention

(1) Definition

For clarity, the terms and expressions used in the description and the attached claims, is determined as described below.

Used herein, the term "analgesia" means the attenuation (reduction) or lack of sensitivity to pain, indicating, in particular, the relief of pain without loss of consciousness.

Used herein, the term "animal" includes mammals and memleketim and, in addition, includes people and nechelovekopodobnoe mammals.

Used herein, the term "AUC" means the area under the curve, which is a measure of the degree of absorption of the compounds in the body.

Abbreviations used here "AUCo-", "AUC(O-infinity) and AUC(O-back.)" mean area under the curve "plasma concentration-time" between the time points of zero hours and infinity.

Used herein, the abbreviation "Cthe Mactan, which is the result of a combination of more than one ingredient.

Used herein, the abbreviation "End" means the concentration.

Used herein, the abbreviation "CV" means the coefficient of variation and is a function of the standard error of the mean. It indicates the variability of the test and it is calculated by dividing the standard error (SE) on the measured value of concentration and multiplying by 100%.

Used herein, the abbreviation "DMF" means dimethylformamide.

Used here, the term "DMSO" means dimethyl sulfoxide.

The abbreviation "DSC" means Differential Scanning Calorimetry.

Used herein, the expression "EC50concentration" means such concentration of compounds or drugs that are needed to achieve 50% maximal biological response.

Used herein, the expression "ED50dose" means the dose of a compound or drug that provides a biological effect, such as producing analgesia, 50% of animals who enter this compound or drug.

Used here abbreviato chromatography high pressure (permissions).

Used herein, the term "mole" and "kilomole" means one thousand moles.

Used herein, the abbreviation "LCL" means the lowest level of trust.

Used herein, the abbreviation "Min" or "min" means minutes.

Used herein, the abbreviation "GHSD, MPLC" means liquid chromatography medium pressure.

Used herein, the abbreviation "MRT" means the average retention time determines the period of time during which the connection remains in the body.

The abbreviation "n" or "N" used in relation to data, means the number of messages or patients experience specific experience (experiment).

Used herein, the abbreviation "NF" means the National Specifications Compositions. (National Formlulary Specifications).

Used herein, the term "oxaprozin" means 4,5-diphenyl-2-oxazolepropionic acid, which has the following chemical structure:

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Used herein, the abbreviation "%CD" means % colloidal silicon dioxide.

Used herein, the abbreviation "%CS" means % corn starch.

Used herein, the abbreviation "%OKHA" means % potassium salt oxaprozin.

Used herein, the expression "pharmaceutically acceptable" refers to those compounds, products, compositions and/or dosage forms which are, within the limits of the medical assessment, are suitable for use in contact with tissues of animals without excessive toxicity, agitation, allergic reactions or other problems or complications that are consistent with the relation reasonable benefit/risk.

Used here, the expression "potassium oxaprozin and potassium salt oxaprozin" means potassium salt of 4,5-diphenyl-2-oxazolepropionic acid, which has the following chemical structure:

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Used herein, the abbreviation "QD" means once a day.

Abbreviations used here "RPM" or "rpm" ("rpm" means revolutions per minute.

Used herein, the abbreviation "CCA" ("RSD") means the percentage relative standard deviation, which is a variation within a population relative to the average of the same population.

Used herein, the abbreviation "C. O." ("SD" or "Std Dev") means the standard deviation from the mean.

Abbreviations used here "SEM" and oznacza the e deviation and N is the number of samples.

Used here, the expression "sodium oxaprozin" and "sodium salt oxaprozin" means sodium salt of 4,5-diphenyl-2-oxazolepropionic acid, which has the following chemical structure:

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Used herein, the expression "therapeutically effective amount" means an amount of compound, product or composition which is effective dose for eliminating or reducing the intensity of pain in the animal, eliminating or reducing inflammation in an animal or to produce some other desired therapeutic effect, in relation to "reasonable benefit/risk" applicable to any treatment with the medicinal product.

Used herein, the abbreviation "Tmax"(Tmaxmeans the time of maximum plasma concentration and mean observed value obtained by determining the time at which the maximum concentration in plasma, as is well known to specialists in this field of technology.

Used herein, the abbreviation "Tnand tnmean half-life (half-life) connection.

Used herein, the term "TRIS" means Tris(hydroxymethyl)aminomethan, Cote oxaprozin" means Tris(hydroxymethyl)aminomethane salt of 4,5-diphenyl-2-oxazolepropionic acid, which has the following chemical structure:

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Used herein, the abbreviation "UCL" means the highest level of trust (privacy).

Used herein, the abbreviation "USP" means the Pharmacopoeia of the United States.

(2) the Description of the invention

In one aspect, the invention provides a pharmaceutical preparation for oral administration, pharmaceutically acceptable and which provides a therapeutic response in the tablet, drip or other molded form, which includes a salt of potassium, sodium or Tris salt oxaprozin.

In another aspect, the invention provides a pharmaceutical preparation for oral administration, pharmaceutically acceptable and which provides a therapeutic response in the tablet, drip or other molded form, which includes: (a) a salt of potassium, sodium or Tris salt oxaprozin as an active ingredient; (b) suitable lubricating substance.

In another aspect, the invention provides a pharmaceutical preparation for oral administration, pharmaceutically acceptable and which provides a therapeutic response in the tablet, drip or other molded F. DATASHEE lubricating substance; and (C) a suitable binder.

In another aspect, the invention provides a method to eliminate or reduce pain in an animal and methods of treatment of inflammation associated with inflammatory diseases such as rheumatoid arthritis and osteoarthritis, and related diseases and conditions in animals, including the introduction of a pharmaceutical composition of the present invention described herein, the animal.

The pharmaceutical compositions of the present invention can specifically be for oral administration in a solid dosage form such as tablet, caplet or other molded shape.

The pharmaceutical preparations of this invention may contain small amounts of metallic stearates (less than 0,976% by weight of the total tablet or other molded forms containing such a composition, such as grease-stearates of magnesium, calcium and zinc, in order to prevent a detrimental effect on the disintegration and/or dissolution of tablets, drips or other extruded forms of these compounds. Preferably, the pharmaceutical preparations of the present invention do not contain any metallic stearates. If the pharmaceutical preparations of the present invention contain STE molded form of a pharmaceutical preparation, and more preferably to be not more than 0.5% of the total mass.

The pharmaceutical preparations of this invention may contain minor amounts (less than 2% by weight of the total tablet or other molded forms containing such a composition) of the binder is methyl cellulose, in order to prevent any detrimental effect on the disintegration and/or dissolution of tablets, drips or other extruded forms of these compounds. When the percentage greater than this, methylcellulose forms a gel on the tablet, which is observed visually and which prevents the dissolution of the tablets. Preferably, the pharmaceutical compositions of this invention do not contain methylcellulose.

The preparations of the present invention suitable for oral administration may be in the form of pills, tablets, drips or other extruded shapes, each of which contains a predetermined amount of the active ingredient.

The pharmaceutical preparation of this invention (pills, tablets, caplet and so on ) may contain the active ingredient (salt of potassium, sodium or Tris salt oxaprozin), optionally mixed with one or more pharmaceutically acceptable carriers and diluents, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid;

(2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia;

(3) humectants, such as glycerol;

(4) dezintegriruetsja tools, such as agar-agar, calcium carbonate, potato starch or tapioca starches, alginic acid, certain silicates and sodium carbonate;

(5) means, retarding dissolution such as paraffin;

(6) absorption accelerators, such as Quaternary ammonium compounds;

(7) wetting agents such as cetyl alcohol and glycerol monostearate;

(8) absorbents, such as kaolin and bentonite clay;

(9) lubricants, such as talc, calcium stearate, a small amount of magnesium stearate, calcium stearate, zinc stearate, solid polyethylene glycols, sodium lauryl sulphate and mixtures thereof;

(10) glidant (agents that improve the slip), such as colloidal silicon dioxide;

(11) antiadhesive (anti-caking), such as colloidal silicon dioxide;

(12) dyes, such as food, drug and cosmetic dye yellow #6;

(13) means for regulating the pH (tabularasa funds), that is something as calcium acetate phthalate;

(16) covering means, such as hypromellose and OpadryBlue;

(17) sweetening means, such as sugar;

(18) flavouring (flavouring) tools, such as peppermint and mint spicate;

(20) preservatives, such as bottled hydroxy-anisole;

(21) antioxidants, such as ascorbic acid or ethylenediaminetetraacetate;

(22) granulating means, such as methylcellulose; and

(23) surfactants, such as polyoxyl 40 stearate, sodium lauryl sulfate and other ingredients.

The most preferred pharmaceutical composition of this invention is the composition of the tablets with potassium salt oxaprozin presented in table.12.

The pharmaceutical preparations of the present invention can also be used in the form of veterinary drugs.

The components of the pharmaceutical preparations of the invention and their ranges

Active tool

The active tool component (potassium, sodium or Tris salt oxaprozin) pharmaceutical preparations of the present invention, is the ingredient that gives the desired therapeutic response, such as pain reduction, required therapeutic response is not received. If, on the other hand, too many active funds present in these drugs, therapeutic response may be too large or it can lead to one or more undesirable side effects. Thus, pharmaceutical preparations of the present invention contain a sufficient number of active funds in order to obtain the desired therapeutic response in a patient, such as pain reduction or reducing inflammation, but this number is less than the amount that could have a disproportionate response and/or could cause one or more undesirable side effects.

The range of content of active funds in percent by weight of the total tablet that is commonly used in the pharmaceutical preparations of the present invention is from about 37,14% to about 100%, more preferably from about 60% to of 99.75%, even more preferably from about 70% to 90%, and most preferably from about 80% to 86%.

Binder

Component, a binder of some pharmaceutical preparations of the present invention, contributes to the formation of these drugs in tablet or other compressible form using fur is aulnoy pills, caplet or other molded shapes. If these drugs are used insufficient amount of binder, it is impossible to obtain extruded granules in large commercial scale. If, on the other hand, apply too much binder, the resulting tablets are too hard and therefore cannot disintegrate and/or dissolve properly within a certain time. Thus, pharmaceutical preparations of the present invention, which contain a binder, contain a sufficient amount of binder to education is capable of compressing the granulate into a large commercial scale, but this number is less than the amount which could lead to tablets or other extruded shapes, which is too hard and therefore do not disintegrate or dissolve properly within a certain period of time.

Group I. a Polymeric binder

Soluble mecellose binder

i.e., polyvinylpyrrolidone, polyvinyl alcohol

Cellulose binder,

i.e. methylcellulose, hypromellose, carboxymethyl cellulose, etc.

Group II. Polysaccharides

Natural resins, i.e., acacia, alheim mic-rocarpium gum), macrogol stearate, fruit of the baobab, etc.

Sugar and starches, i.e. sucrose, fructose, dextrose, pre gelatinizing corn starch, metastable amylose, amylodextrin, maltodextrins, cyclodextrins, Kilani etc.

Group III. Polyols, i.e., glycerin, sorbitol, mannitol, xylitol, etc.

Group IV. Proteins, i.e., gelatin, casein, etc.

In the study of polymeric binder is polyvinylpyrrolidone, apparently, has no restrictions for use and you can use it as much as filler, how much can really be used to obtain tablet real size. Polyvinyl alcohol is probably the upper limit for use at 20% wt/wt.

The results of dissolution are presented in table. 13 and 14.

The conclusion that can be made for the soluble recellular binder, is that they are effective up to the maximum limits of 20 to 30% wt/wt for compounds with oxaprozin potassium. For cellulosic polymer binder as representatives of this class choose hypromellose and the upper limit to define it according to the digestions, to depict the 5 and 20% wt/wt.

Acacia is chosen as representative of the normal natural resin. The results of dissolution are presented in table. 17 and 18.

The results indicate that natural binder resin can be effective up to 17.5-20% wt/wt, but not outside this range.

Data were obtained for the two fillers from the group of sugars and starches. Pre gelatinizing corn starch is not beyond the scope of the basic patent. You may receive a product that meets the requirements at 30% wt/wt. Sucrose was also investigated. The filler has been very effective at getting at 3,9% wt/wt level using wet granulation.

When you try to use 30% wt/wt sucrose, using wet granulation, the wet granulate froze in the oven during drying.

Tablets containing 30% wt/wt sucrose, receive, adding dry sucrose. The result is a very soft tablets (0,9-2,4 KS(Kr)). These pills are dissolving for the reason (following the logical conclusion that the combination of the two processes should lead to the production of tablets up to 30% and above. The results of dissolution of tablets containing 30% of dry binder are presented in TA is akharov and starches, there is no maximum limit and you can use the same filler, how practically can be used in the preparation of tablet real size.

As the polyol for the study was selected glycerin. The dissolution was not a limiting factor for functional use of this filler. Sticking started to happen when a content of 20% wt/wt. Adding from 20 to 30% paste is formed only by adding glycerol. When 30% of the paste is dried and milled. Tablets are made by rotating the press manually. It should be noted that in that case, if you are able to overcome the adhesion, there should be an upper limit associated with the dissolution. The results for both 20% and 30% are presented in table. 20 and 21.

Conclusion for polyols is that if the adhesion can be overcome, there is no limit to % level, which may be used in the composition. If not, then the upper limit is between 20 and 25%.

In the study of protein binding upper limit is determined by the quantity of solvent which can be transferred to the drug substrate and in which it is possible to carry out granulation. The reason is that protein binder in need of hydration, to lastwow who was salsa acceptable and are presented in table. 22.

The conclusion is that the binding protein can be used up to 5% in the composition.

The binder and the ranges of their percentage by weight of the total tablet that can be used in the compositions of this invention include corn starch USP (preferably from 0% to 10%), pre-gelatinizing corn starch (preferably from about 0% to 99%, more preferably 0.25 to 30% and most preferably 0.5 to 5%), sucrose (preferably from about 0% to 85%), polyvinylpyrrolidone (preferably from about 0% to 20%), methylcellulose (varieties with different viscosity) (preferably from about 0% to about 2%), sodium carboxymethylcellulose (grade low viscosity) (preferably from about 0% to 2%) and ethylcellulose (varieties with different viscosity) (preferably from about 0% to 2%).

Lubricants

Component lubrication of some of the pharmaceutical preparations of the present invention contributes to popping pills or other molded shape, which is formed in a mechanical press, press, without destruction. If these drugs are used too little lubrication, policy, or damage to the press for tableting. If, on the other hand, these drugs are used too much grease, it may affect disintegration (decay) of tablets and/or dissolution and, thus, to reduce the effect of the active funds. Grease may also inhibit the binding (adhesion) of the compositions in a mechanical press, so the ability to be compressed into the tablet decreases. Thus, the preparations of this invention, which contain a lubricating substance, contain a lubricating substance in a quantity sufficient to prevent popping pills or other molded form of a mechanical press without damage, but this number is less than the number that would adversely affect the path that the tablet disintegrates and/or dissolves, or which could inhibit the binding of compounds.

In most cases, water-insoluble lubricant is preferred for use in this invention than water-soluble lubricant, because the former are more effective as lubricants.

A partial list insoluble (or slowly soluble) lubricants include stearic acid, sodium stearate, steer the ASS="ptx2">

Was studied stearic acid and found that the maximum level of use on the basis of dissolution, is between 17.5 and 20%. Also was studied stearate, and found that it has the maximum level of less than 1%. Magnesium stearate is insoluble lubricant and, as you know, the magnesium ion forms an insoluble precipitate with the drug. I believe that stearic acid is a slowly soluble lubricant. Sodium stearate and potassium stearate are slowly soluble ingredients. Calcium stearate, zinc stearate, talc, polyethylene glycol 6000 and glyceryl begent, all are insoluble. Sodium stearate is selected as the other slowly soluble candidate for study and talc and calcium stearate are chosen as insoluble candidates for study.

There were obtained tablets with sodium stearate with excellent appearance and hardness. Dissolution was the only limiting criterion and it is found that the maximum level for the use of this substance is 20% (see tab. 23).

It was found that the upper limits for the talc and calcium stearate are 15% wt/wt and 5% wt/wt, but what I tablets, cooked with talcum powder was in the range of from 2.5 to 7.0 CC (CR) and for tablets containing calcium stearate, ranged from 2.9 to 4.6 COP. The data obtained by dissolving presented in table. 24 and 25.

The conclusion that can be made to slowly soluble substances, i.e., stearic acid, stearates, sodium and potassium, is that dissolution is the rate-limiting factor and that up to (their content) from 17.5% to 20% wt/wt, these substances are well function as lubricants. The conclusion that can be done to remove insoluble stearates, is that calcium stearate operates differently than magnesium stearate. For stearate dissolution is the rate-limiting factor. For calcium stearate the compressibility becomes the limiting factor. It can be assumed that the stearate of zinc will act similarly to calcium stearate, and that these two elements have an upper limit less than 5% in the composition. Other insoluble lubricants should act like talc, and the compressibility becomes a problem until the dissolution, when the upper limit is 15%. The ability to pressing decreases much faster for insoluble lubricants than for soluble is and can be observed in 15% of talc and 5% for calcium stearate.

Excluding hydrogenated castor oil and glycerinate, any water-insoluble lubricating substance can be used in pharmaceutical preparations of the present invention. Water-insoluble lubricant and the ranges of their percentage of the total weight of the tablet, which can be used in the preparations of this invention include magnesium stearate, calcium and zinc (less than 0,976%, preferably from about 0% to about 0.25%, most preferably 0%), stearic acid (preferably from about 0% to about 17.5%, more preferably from about 1% to about 4%, most preferably from about 1% to about 2%), gidrirovannoe vegetable oil (preferably from 0% to 5%, more preferably from about 0.25% to about 2%), talc (preferably from about 0% to about 10%, more preferably from about 1% to about 5%).

There are many soluble lubricants. The following represents a partial list: boric acid, sodium benzoate, sodium acetate, sodium chloride, potassium chloride, DL-leucine Hcl, carbowax-4000, sodium oleate, sodium lauryl sulphate, magnesium lauryl sulphate, glyceryl palmitate stearate, PEG (PEG) begent, sodium laurelhurst, sodium, stearyl stearilfumarat. All three are determined to provide an acceptable dissolution profile at 30% wt/wt level in the composition. Sodium lauryl and sodium fumarate with 30% wt/wt level in the drug provide tablets with a hardness below 5 KS. The results obtained show that this class of lubricants does not slow down the dissolution alone or in combination with other lubricating substances can be used in any level where you can get acceptable lubrication and the hardness of the tablets. Tablets with sodium chloride show some adhesion in the hardness range from 7 to 13 KS, but it is not observed in hardness between 15 and 20 KC. Hardness for tablets is not a problem in the case of this filler. At 30% wt/wt level in the structure have the following results for dissolution oxaprozin potassium: N=6 for all tests except where noted (see table. 26-28).

The conclusion that can be made for this class of soluble lubricants, using (them) in the preparation of tablets with oxaprozin potassium, is that any level of these fillers, which will give acceptable tablet both in appearance and hardness, will also provide priesley lubricants is determined by the size of the tablet, receivable. If the 30% levels of filler can be achieved in the composition and satisfied the criterion of solubility, it is considered that there is no upper limit for the use of particular lubricants or binders and compositions can be used as much filler as is typically used in the preparation of tablet real size.

Water-soluble lubricant and the ranges of their percentage by weight of the total tablet that can be used in the compositions of this invention include sodium dodecyl sulfate (preferably from about 0% to about 20%, more preferably from about 0% to about 10%, most preferably from about 0% to about 5%), and sodium fumarate (preferably from about 0% to about 5%, more preferably from about 0.25% to about 2%, most preferably from about 0.5% to about 1%).

It is also possible to combination of more than one of the above-described lubricating substances in them is described ranges, for example magnesium stearate about 0.25% stearic acid, about 1%. In addition, you can combine one or more of the above-described lubricants with small amounts of other lubricants, such as boric acid, sodium benzoate + sodium Chat, magnesium lauryl sulphate, glycerol palmitate stearate, glyceraldehyd, paraffin, PEG (PEG) begent, sodium, stearylamine, magnesium laurylsulfate, sodium stearate and ucuuba (ucuuba) resin (seeds of virola surinamensis).

Glidant

Optional-glidant pharmaceutical preparations of the present invention facilitates the flow of granulate in a mechanical press, which is sufficient for maintaining control of the same weight from tablet to tablet. It also helps to prevent adhesion of the tablet or other molded shapes of the upper and lower punches of the press. If the level of glidant too low, the oscillation of the mass from tablet to tablet may be too large, and tablets can be heterogeneous. If, on the other hand, the level of glidant too high, it will prevent the binding characteristics of the tablets, and the physical quality of the pill may start to decline (harmful influence on the compressibility of the composition into tablets and/or dissolution of any of the obtained tablets). Thus, the preparations of the present invention optionally contain a sufficient number of glidant in order to provide for granulate containing drugs, mechanical press, Dostal adhesion of the tablet to the upper and lower punches of the press, but this number is less than the quantity that can inhibit the binding characteristics of the tablets.

In the preparations of the present invention does not necessarily use any glidant. Glidant and their ranges of percentage by weight of the total tablet that can be used in the preparations of this invention include talc (preferably from about 0% to about 10%), corn starch USP (preferably from about 0% to about 10%), pre-gelatinizing corn starch (preferably from about 0% to about 10%) and silicon dioxide (preferably from about 0% to about 0.5%).

Antiadhesive

Optional - release agent of the pharmaceutical preparations of the present invention facilitates the flow of granulate in a mechanical press, sufficient to maintain control for constant mass from tablet to tablet. It also helps to prevent adhesion of the tablet, or other molded shapes of the upper and lower punches of the press. If the level of antiadhesive is too low, the oscillation of the mass from tablet to tablet may be too large, and tablets can be heterogeneous. If, on the other hand, the level Antigua tablets may begin to decline (may affect the ability to pressing the composition into tablets and/or dissolution of the obtained tablets). Thus, the preparations of the present invention optionally contain a sufficient number of antiadhesive to provide for granulate, compositions containing, in a mechanical press, sufficient to maintain control for constant mass from tablet to tablet and to prevent adhesion of the tablet to the upper and lower punches of the press, but this number is less than the quantity that can inhibit the binding characteristics of the tablets.

In the preparations of the present invention is optional, you can use any release agent. Antiadhesive and their ranges of percentage by weight of the total tablet that can be used in the preparations of this invention include talc (preferably from about 0% to about 10%), corn starch USP (preferably from about 0% to about 10%), pre-gelatinizing corn starch (preferably from about 0% to about 10%) and silicon dioxide (preferably from about 0% to about 0.5%), DL-leucine (preferably from about 0% to about 10%), sodium lauryl sulfate (preferably from about 0% to about 10%) and metallic stearates, such as the stearates of magnesium, calcium and zinc (less than 0,976%, preferably from okanta - filler pharmaceutical preparations of the present invention, is to fill the space. Thus, the percentage of filler used is not significant, except that the use of insoluble fillers in too many in the tablet can slow raspadaemost tablets in time and, thus, adversely affect the dissolution. The person skilled in the art is able to determine this quantity in respect of a particular filler.

Insoluble fillers and their ranges of percentage by weight of the total tablet, which optionally can be used in the preparations of this invention include starches such as corn starch, potato starch, tapioca starch and rice starch (from about 0% to about 99%, most preferably from 0% to 30%), modified starches such as sodium starch glycolate, and pre-gelatinizing corn starch (from about 0% to about 99%, most preferably from 0 to 30%) and microcrystalline cellulose (from about 0% to about 49,29%preferably from about 0% to about 27%, most preferably from about 0% to about 12.7%).

In preparatorily and their ranges of percentage by weight of the total tablet, which can be used in the preparations of this invention include lactose, sucrose, dextrose, mannitol and sorbitol, each (from about 0% to about 65%, preferably from about 5% to about 50%, most preferably from about 8% to about 15%).

Disintegrator

Action optional component of the cage mill of pharmaceutical preparations of the present invention is to facilitate dezintegratsii (raspadaemosti) tablets (the ability of tablets to fracture into small pieces), pressed from these compositions. The disintegrator and the ranges of their percentage of the total mass that can be optionally used in the compositions of this invention include corn starch, NF purity 21, croscarmellose Na, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, polacrilin (polacrilin) potassium IRP-88, sodium starch glycolate, each from about 0% to about 10%, preferably from about 1% to about 5%, most preferably from about 2% to about 3%.

(3) the Usefulness

Drugs potassium, sodium or Tris salt oxaprozin of this invention are useful as analgesics for the treatment of pain in animals and as anti-inflammatory drugs for patients of diseases and conditions.

New pharmaceutical preparations of this invention can be used to treat inflammation in an animal and for treatment of other inflammation disorders, such as analgesics (analgesic agent) for the treatment of pain and headaches, or as an antipyretic (febrifuge) for the treatment of fevers. For example, a new pharmaceutical preparations of this invention may be useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, osteoarthritis, and juvenile arthritis. Such pharmaceutical preparations may be useful to treat gastrointestinal conditions such as the syndrome of irritated large intestine, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The pharmaceutical preparations of this invention may be useful for treating inflammation in such diseases as vascular diseases, migraleve headaches, diving nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, diabetes type I diabetes, myasthenia gravis heavy (myasthenia gravis, sarcoidosis, nephrotic Sindragosa after injury, myocardial ischemia, etc.

The pharmaceutical preparations of this invention are useful as anti-inflammatory drugs, such as for the treatment of arthritis, with the additional benefit (additional benefit), which consists in the manifestation of a significantly less harmful side effects and good gastrointestinal tolerance.

When developing any input oral solid pharmaceutical preparation which contains the active ingredient for the treatment of pain, the preferred goal is to achieve the highest content of active ingredient in dissolved state, thereby introducing into the bloodstream of the patient in the shortest period of time and, as a result, the occurrence of the commencement of the active ingredient in a relatively short period of time, such as one hour. The pharmaceutical preparations of the present invention typically have a characteristic consists in the fact that about 75% of the active ingredient (potassium, sodium or Tris salt oxaprozin) becomes soluble in the environment of phosphate buffer within about 30 minutes, and some of these compounds have about 95% of the active ingredient dissolved in this environment for about 30 minutes. Ecstasy for tablets, contains only the active ingredient (potassium, sodium or Tris salt oxaprozin), have characteristic consists in the fact that about 80% of the active ingredient becomes soluble in the environment of phosphate buffer for 15 minutes. Other experiments on the dissolution described herein below demonstrate that the proposed pharmaceutical formulations for tablets containing potassium salt oxaprozin and containing magnesium stearate in the percentage by weight of the total tablet that is equal to or greater than 0,976%, do not have the above properties. These experiments also show that the preferred pharmaceutical preparation of the present invention, which does not contain magnesium stearate, usually contains about 90% of the active ingredient that is soluble in the medium of phosphate buffer for about 15 minutes and about 100% of the active ingredient is dissolved within 30 minutes.

(4) the Means of obtaining

In General, the pharmaceutical preparations of the present invention can be obtained by the methods illustrated in the General schemes of the reactions below, or modifications of them, using the available source materials, reagents and conventional synthesis procedures.

Oxaprozin contains an acidic functional and with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic potassium, sodium and Tris salts oxaprozin with attached inorganic and organic base. These salts can be obtained by way of the final isolation and purification oxaprozin or by individual interaction cleaned oxaprozin in its free acid form with a suitable base such as the hydroxide, carbonate or bicarbonate pharmaceutically acceptable cation-metal, with ammonia or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative examples of salts of alkaline or alkaline earth metals include lithium salts, sodium, potassium, calcium, magnesium and aluminum, etc., Representative examples of organic amines useful for the formation of salts joining the Foundation, include ethylamine, diethylamine, Ethylenediamine, ethanolamine, diethanolamine, piperazine, etc., See, for example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm.Sci., 66:1-19 (1977), which is here referred to.

Methods of obtaining pharmaceutical preparations of this invention include the implementation phase binding (Association) of active ingredient (potassium, sodium ilno, with one or more accessory ingredients. In General, products derived through the implementation of a uniform and tight binding of the active ingredient with other ingredients of the composition and, optionally, with one or more other ingredients with liquid carriers or finely ground solid carriers, and then the molded product, for example, using a mechanical press in pills, tablets, caplet or other extruded forms of drugs.

The General reaction Scheme 1 (see Fig. 1 shows the synthesis of various salts oxaprozin described here (sodium, potassium and Tris salts oxaprozin). Oxaprozin in its acid form is commercially available, for example, from Katwijk Chemi BV, Steen-bakkerstraat, NV.

In a vessel of stainless steel or coated glass download oxaprozin, and then isopropanol (isopropyl alcohol). The mixture is heated to approximately 70oAnd the corresponding solution of aqueous base (e.g. potassium hydroxide, sodium hydroxide or Tris hydroxide) is added to the mixture until then, until it reaches the desired end point pH (pH 9-13). In order to achieve complete conversion of the acid salt, at least one stoichiometric equivalent SEL is the treatment part of the acid oxaprozin. In this case, the resulting product will be a mixture of acid oxaprozin and salt oxaprozin.

The resulting solution is filtered by a method known to specialists in this area to ensure free from particles of the product. Part of the volume of the solvent is removed by distillation at atmospheric pressure by way of well-known experts in this field. (The distillate is an azeotrope of isopropanol and water. Water remaining in the reaction mixture leads to the loss of output due to the solubility of the salt oxaprozin in the water. The amount of distillation is based on the economic analysis that compares the cost of the distillation towards the exit). After distillation add fresh isopropanol to the reaction mixture at the boiling temperature under reflux. The solution is cooled to cause crystallization of the product. The product is separated by centrifugation, a method known from the prior, washed with isopropanol and dried in a fluidized bed or in a vacuum drying method known to specialists in this field at a temperature not exceeding 120oC.

The General reaction Scheme 2 (Fig. 2) shows getting pressed formats which is in powder form, in capable of pressing the granulate can be performed in any mixer with a high speed/high shear with a spray (spray wand) and chipping machine. Dry potassium oxaprozin, sodium oxaprozin or Tris oxaprozin placed in a mixer and mix with the main mixer and chippers at low speed over a period of time sufficient to destroy any lumps that may be present in the source material. For those of pharmaceutical preparations of the present invention, which contain a binder, the binder suspension, such as pre-gelatinizing corn starch, prepared in a blender propeller type with a sufficient quantity of purified water, getting capable of spraying a solution of suspension. Binder should be added slowly to avoid lumps in the slurry. It is preferable to include in the mixture an additional 5% or so of the binder, which will remain in the mixer until the end of this process, in a way known to specialists in this field. The binder suspension is heated in a suitable heating vessel such as a reactor with jacket, heated by steam, and is maintained at approximately 53oC. Arial, using neposlushnoy the spray system, method, well-known experts in this field. Put all the liquid at once, the mixer works as long until it forms granules. If at the end of the granulation phase product looks lumpy, consisting of the pieces, all the granules may be sieved wet vibrating granulator or mill way, well-known experts in this field, to the stage of drying.

Drying of the product granulation can be performed in any fluidized bed dryer suitable size method, well-known experts in this field. The wet granulate is placed in a container for a product and layer transfer in fluidized condition. The temperature of the drying air is approximately 75oC. the Granulate is dried to a moisture content of less than 2% wt/wt (less than 2 g of water per 100 g of the final product granulation). After the moisture content reaches the set value, the granulate is sieved through a sieve #12 or other suitable sieve method, well-known experts in this field. For grinding can fit any equipment that can be integrated sieve #12.

Dry mixing can Omero granules are loaded into a mixer and add to this mixture a suitable amount of all optional ingredients such as glidant and antiadhesive. Include a mixer and stirred for approximately 10 minutes. For those pharmaceutical compositions of the present invention, which contain a lubricant, this lubricant, such as stearic acid, sieved through a sieve of 30 mesh or other suitable sieve method, well-known experts in this field, and add to the mixer. Final mixing time is approximately 7 minutes, the mixture is then removed from the mixer.

Pressing the obtained composition in tablets, caplet or other pressed oral form, can be implemented on any suitable media for tabletting method, well-known experts in this field, such as a rotary machine for tabletting capable of supporting snap 0,3261" x 0,7480" (0,8283 cm x 1,899 cm). The granules are loaded into the hopper for tabletting machine, and the machine begins to produce tablets, caplet or other extruded form for oral administration which have the desired physical characteristics (specifications) for the final product. These characteristics include acceptable raspadaemost, dissolution, hardness, size, deviation (variation) of the weight and fragile (brittle).

Neonatal as Opadry, which can be obtained from the use, Inc. (West Point, PA), can be accomplished by way of well-known experts in this field, in any perforated tub with a side opening, equipped with a spray system air. This coating makes the tablet more easily swallow them and improves their pharmaceutical appearance. Tablets are loaded into the machine and turn up the heat to heat the layer tablets. The coating process is performed at a temperature that is preferably at least 50oC. Prepare an aqueous solution for coating and put on the pill at a speed of baths, approximately 7 rpm (revolutions per minute). When tablets will take reasonable appearance will take pharmaceutically desirable appearance), and will bear an appropriate amount of solution, the coating process is complete.

Conditions for the exercise of individual stages in each of the General schemes of the reactions presented above are conventional, well-known and can vary widely.

For the synthesis of potassium, sodium or Tris salt oxaprozin can also be used in other ways known in this field.

Because salt oxaprozin are photoacustic who must undergo excessive exposure to light during the process of obtaining pharmaceutical preparations of the present invention.

Besides inert diluents, the oral compositions can also include adjuvants, such as humectants, emulsifying and suspendresume tools, sweetening means, corrigentov, dyes, substances that give a smell, and preservatives.

(5) the Dosage and method of application

The pharmaceutical compositions of the present invention is used to treat pain, inflammation and/or associated with inflammatory disorders in animals. The attending physician or veterinarian specialists in this field can easily identify, suffering or not suffering from a specific patient from pain, or inflammation, or a disease associated with inflammation.

The pharmaceutical compositions of the present invention, which typically include potassium, sodium or Tris salt oxaprozin as the active ingredient, by itself, in a mixture with a pharmaceutically acceptable lubricant, or in a mixture with a pharmaceutically acceptable lubricant and a pharmaceutically acceptable binder, and, optionally, with one or more other compounds, drugs, fillers or other therapeutic or non-therapeutic substances used therapeutically and, therefore, should generally use is to be "acceptable" in the sense that it is compatible with other ingredients of the compositions and harmless for the patient.

Acceptable dose and the form of the introduction of the pharmaceutical compositions of this invention should choose methods that correspond to conventional pharmaceutical practice.

The pharmaceutical preparations of this invention may be specially formulated for oral administration in solid, extruded form and prepared in pharmaceutically acceptable dosage forms by standard methods known to experts in this field.

The actual dose levels of active ingredients in the pharmaceutical compositions of the present invention (potassium, sodium or Tris salt oxaprozin) may be varied to obtain an amount of active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without showing toxic effects on the patient.

The selected dose is usually dependent on a number of factors, including the activity of the specific salt used oxaprozin, route of administration, time of administration, rate of excretion of the specific salt oxaprozin to be used, the intensity of pain, inflammation or disorders associated with inflammation, protoliterate in combination with the particular salt used oxaprozin, age, sex, weight, condition, General health and prior medical history of the patient to be treated, and like factors well known in the medical fields.

The attending physician or veterinarian of average skill in this field can easily determine and prescribe the effective amount of the pharmaceutical composition required to relieve or reduce the intensity of specific pain patient, inflammation or disorders associated with inflammation. For example, the physician or veterinarian could start doses of the compounds of the invention used in the pharmaceutical composition at levels lower than the level required to achieve the desired therapeutic effect and gradually increase the dose until then, until you reach the desired effect.

In General, a suitable daily dose of a pharmaceutical preparation of the present invention is that amount of a pharmaceutical composition, which is the lowest dose effective to obtain a therapeutic effect. This effective dose is usually dependent on the factors described above. Usually, the patient is a mammal is administered the dose levels in the range from about 0.001 mg to okong and most preferably from about 1200 mg to about 1800 mg of the pharmaceutical composition in the day. However, the total daily consumption of the pharmaceutical compositions of this invention should be determined by the attending physician or veterinarian, not beyond reasonable medical evaluation.

If necessary, the effective daily dose of the active compound (potassium, sodium or Tris salt oxaprozin) may be administered as two, three, four, five, six or more subdot, administered separately at appropriate intervals throughout the day, not necessarily in standard dosage forms.

The preparations of this invention are compositions that are suitable for oral administration. The formulations may be presented in a standard dosage form. The amount of active ingredient (potassium, sodium or Tris salt oxaprozin), which can be combined with the carrier or other material, to obtain a single dosage form, usually varies depending on the host to be treated, the specific route of administration and all other factors described above. The amount of active ingredient that may be combined with the carrier or other material, to obtain a single dosage form, is usually this number is based on a hundred percent, this amount generally ranges from about 1 % to about 100 % active ingredient, preferably from about 50 % to about 95 %, most preferably from about 70 % to about 90 %, preferably about 83%.

Although various aspects of the present invention is described here in sufficient detail, the experts in this field numerous obvious modifications and variations that fall within the scope of the essence of this invention. These modifications and variations are within the scope of the here described invention and the appended claims.

(6) Examples

The following examples describe and illustrate the methods for obtaining preparations of the present invention, as well as other aspects of the present invention, including failed experiments described here above, and the results in more detail. Where appropriate, describes as explained various aspects of the present invention and the existing methods of various aspects of the present invention. These examples are intended only to illustrate the present invention and do not limit its scope or essence. For specialists in this area it is obvious that to obtain pharmaceutical compositions of this izopet is the reamers.

In these examples, all parts are mass, unless otherwise noted.

All materials used in examples of the commercially available equipment.

Unless otherwise noted in a specific example, all of the source materials used in the examples are commercially available. The sources for these initial substances and equipment used in the examples include the Sigma Chemical Co. (St. Louis, MO), Aldrich Chemical Co. (Milwaukee, WI), Lancaster Synthesis (Windham, NH), Fisher Scientific (Pittsburgh, PA), Boehringer Mannheim Biochemicals (Indianapolis, IN), Fluka Chemical Corp. (Ronkonkoma, NY), Chemical Dynamics Corp. (South Plainfield, NJ), Pfaitz & Bauer (Waterbury, CT), G. D. Searle & Co. (Augusta, GA), Degussa (Ridgefield, NJ), Witco Corp. (Greenwich, CT) use (West Point, PA), FMC Corp. (Philadelphia, PA), Speciality Minerals Inc. (Easton, PA), National Starch (Bridgewater, NJ), Cabot Corp. (Tuscola, IL), W. R. Grace (Baltimore, MD), Tanabe USA (San Diego, CA), Henkel Corp., (LaGrange, IL), Mal-linckrodt (St. Louis, MO), Karlshamns (Karshamn, Sweden), US Borax (Valencia, CA), Niacet Corp. (Niagara Falls, NY), Cargill Inc. (Eddyville, IA), Morton Salt (Chicago, IL), Union Carbide (Danbury, CT), Strahl & Pritsch (West Babylon, NY), DGF Stoess (Sioux City, IA), Chart Corp. (Paterson, NJ), ISP Corp. (Wayne, NJ), Aqualon (Wilmington, DE), Mendell (Paterson, NY), Quest International (Norwich, NY), Archer Daniel Midland (Decatur, IL), Roquette (Keokuk, IL), Wyckoff Chemical Company, Inc. (South Haven, MI), Solchem Italiana spa (Milan, Italy), Katwijk Chemie bv (Steenbakkerstraat, The Netherlands), Irotec Laboratories (Little Island, Cork, Ireland), Sumita Fine Chemicals Co. Co., Ltd. (Osaka, Japan), Niro Inc., Aeromatic-Fielder Division (Columbia, MD), Lee Industries, Inc. (Philipsburg, PA), Paul A. Mueller Inc. (Springfield, MO), DCI, Iresses - Thomas Engineering (Hoffman Estates, IL), Cadmac Tablet Presses - Key International Inc. (Englichtown, NJ), Stokes Tablet presses (Philadelphia, PA), Thomas Engineering (Hoffman Estates, IL), Natoli Engineering Co. (Chesterfield, MO), Vector Corp. (Marion, IA), O'hara Manufacturing (Toronto, Ontario, Canada), Graco Inc. (Minneapolis, MN), Watson-Marlow (Wilmington, MA) and Spraying Systems Co. (Wheaton, IL). The synthesis methods used in the examples of the starting substances, which are not commercially available, described in the examples.

All patents and publications relating to these examples and is found throughout the description given here for information, without recognizing that they represent prior art.

EXAMPLE 1. Initial unsuccessful experiments conducted when attempting to obtain a product containing potassium salt oxaprozin

(1) the First experiment

In this experiment the acid form oxaprozin in DAYPROdirectly replace potassium salt oxaprozin, getting composition, are presented in table. 29.

As described below receive 12 kg batch of granules in Niro Fielder PMA 1200 high speed/wysokosciowe granulator (Niro, Inc., Aeromatic - Fielder Division, Columbia, MD).

In the car download the potassium salt oxaprozin, microcrystalline cellulose PH 101 and corn starch and a solution of methylcellulose is origanum layer (Niro Aeromatic Fielder Division, Columbia, MA). As soon as the dry mass is sieved through a sieve, combine it with other ingredients. The mixing is performed in Crossflo V-mixer (Patterson-Kelly, Stroudsberg, PA). Test pelletizing spend on a rotary tabletirujut press (Kilian & Co., Horsham, PA). The granulate bad tabletroute because of the strong adhesion of the granules to the walls of the punch. The number of stearate increase from 1.2% to 2.0% wt/wt and overcome the problem of adhesion. Experiments on raspadaemost (disintegration) is carried out in accordance with the U.S. Pharmacopoeia (USP) tablets containing the above composition, in 900 ml of water (purified by reverse osmosis) as the environment in the installation without disk at 37oC. In each experiment on raspadaemost have six tablets at the basket. By visual observation given time interval when the last tablet disappears completely. Tablets of the above composition had a disintegration time in excess of 45 minutes.

The remaining granules are removed from teletrauma machine and divided into two equal parts. To the first part add adjuvant (promoting disintegration), the sodium croscarmelose, in the amount of 3% wt/wt, the second part add the other is then performed in the above-described V-mixer. Both drugs is pressed in the above-described rotary press for tableting.

Experiments on the dissolution was performed in accordance with USP tablets containing any of these drugs, as well as with Dayproin 1000 ml phosphate buffer pH 7.4 as the environment, setting 2 (mixer) at 75 revolutions per minute (rpm) at 37oC. In each experiment by dissolving six tablets experience in six different vessels. Get the percentage of tablets dissolved in a given time interval, calculating the mean and standard deviation method, well-known specialists in this field of technology.

As shown in the table.30 below, tablets compressed from above compositions show poor results in dissolution compared with Daypro.

(2) the Second experiment

In this experiment, as disintegrator add croscarmelose binder and replace hydroxypropylcellulose, getting composition, are presented in table. 31.

Oxaprozin potassium, microcrystalline cellulose PH 101 and the sodium croscarmelose placed in Fuji granulator (Fuji Sangyo Co. LTD, Tokyo, Japan). Include the impeller (mixer) to mix the ingredient which are square in a separate vessel of stainless steel with constant stirring. The resulting solution was spray on dry weight for 12 minutes with the impeller and chippers (shredder). The granulate is dried in an oven with forced circulation of hot air (Blue M, Blue Island, IL). The obtained granulate is sieved through a 14 mesh sieve. The sifted granules, the sodium croscarmellose, microcrystalline cellulose PH 101 and magnesium stearate are mixed in a V mixer. The granulate is removed from the mixer and pressed into rotary machine for tableting. Tablets are pressed without sticking to the walls of the punch.

Experiments on raspadaemost carried out on the tablets the same way as described above. Time raspadaemosti (disintegration) of the tablets was more than 1 hour.

In order to try to improve the disintegration of the tablets, it was decided to add some amount of microcrystalline cellulose. Available granulate is mixed with 50% wt/wt microcrystalline cellulose in a V mixer. The mass of the tablet is increased from 1000 mg to 1500 mg another attempt tabletting, but the tablet of the desired mass to get on the car failed. Compressed tablets 1,300 mg. the disintegration Time for this second part of the tablets was approximately 45 minutes.

Oxaprozin potassium, corn starch and crosspovidone mixed in Fuji granulator. Water spray on blend weight, getting granulate within 12 minutes. The granulate is dried in an oven. The dried granulate is sieved through a 14 mesh sieve. The sifted granules combined in a V mixer with magnesium stearate. The mixture is discharged and transferred into a rotary press for tableting. Attempt tabletting was unsuccessful because of the strong adhesion to the surfaces of the punch press for tableting. In addition, the tablets were destroyed (bulge) (broke while pulling out of a mechanical press).

To save this experiment, it was found that should be added crosspovidone and magnesium stearate in the amounts presented in the table. 33.

Granular, microcrystalline cellulose, crosspovidone and magnesium stearate are mixed in a V mixer. The mixture discharged from the mixer and conduct a test to pelletizing. Tablets do not stick and does not crumble, but it is impossible to obtain tablets with a weight of 1200 mg. Pressed tablets with a maximum weight of 1100 mg.

Experiments on raspadaemost tablets carry out the method described above. The disintegration time of the tablets ranged from 45 minun and grease sodium lauryl binder and replace with povidone K-90, getting the composition presented in table. 34.

Oxaprozin potassium, sodium laurylsulfate and crosspovidone mixed in Fuji granulator. Granulating solution of polyvinylpyrrolidone and get water in a separate container with stirring. The solution for granulation is applied on the mixed mass by slow splashing. In this way the pellet is not formed. To shape the dough, and the experience is complete without further operations.

(5) the Fifth experiment

In this experiment, add disintegrator-starch and talc-glidant binder and replace with povidone K-90, receiving the composition presented in table. 35.

Oxaprozin potassium and crosspovidone mixed in Fuji granulator. Granulating solution of polyvinylpyrrolidone and get water in a separate container. The granulate is dried in an oven and then sieved through a 14 mesh sieve. This final granulate used in the composition shown in table. 36.

The granulate, crosspovidone, microcrystalline cellulose PH 102, pre-gelatinizing corn starch, talc and magnesium stearate are mixed in a V mixer. The mixture is transferred into a rotary machine for tableting. The tests for pelletizing. Tableting bilety on raspadaemost carry on tablets by the way, described here above. The disintegration time of the tablets ranges from 29 to 35 minutes.

(6) the Sixth experiment

In this experiment, was added lactose anhydrous DTG, getting composition, are presented in table. 37.

The granulate, crosspovidone, lactose anhydrous DTG pre gelatinizing corn starch, talc and magnesium stearate are mixed in a V mixer. The resulting mixture was transferred to a rotary machine for tableting. The tests for pelletizing. Tableting was successful tablet not sticking to the surfaces of the punches or was not crumbled in the car. Experiments on the disintegration is carried out on the tablets of the method described here above. The disintegration time for this composition was more than 1 hour.

(7) the Seventh experiment

In this experiment, which was the first successful experiment, the magnesium stearate is a lubricant is removed and the binder used corn starch, getting composition, are presented in table. 38.

Oxaprozin potassium placed in Fuji granulator. In a separate vessel, prepare a paste of starch obtained with the use of water. The starch paste is applied on the mixed mass by means of spraying for 12 minutes. Received g of the acid in a V mixer. The mixture is transferred into a rotary machine for testing by pelletizing, which was successful.

Experiments on raspadaemost carried out on the tablets of the method described here above. The time for disintegration of the drug ranged from 8 to 10 minutes. In addition, this drug have on the dissolution method described above, and the results are presented below.

The results of dissolution for the first successful preparation containing potassium salt oxaprozin

Time, minutes - Potassium salt oxaprozin composition

0 - 0,0

10 - 82,6

15 - not tested

20 - 101,0

30 - 101,1

45 - 101,1

60 - 101,1

EXAMPLE 2. 600 mg tablets containing potassium salt oxaprozin

600 mg film-coated tablets containing potassium salt oxaprozin, was obtained by a method described below.

In a vessel of stainless steel, of a capacity of 2000 gallons, with fixed reflective walls (from Alloy Fab, South Plainfield, NJ), equipped with a multi-speed device for mixing (from Pfaudler, Rochester, NY), download 688 kg (2.35 K-mol) oxaprozin (G. D. Searle & Co., Augusta, GA), and then 3689 kg isopropanol. The resulting mixture was heated to 70o(Using steam with a temperature of 180oWith that act, the t Fisher Controls, Marshalltown, IA). To this mixture approximately 292 kg 45% liquid potassium hydroxide (2,35 K-mol; 1 molar equivalent relative to oxaprozin) up until the final pH reaches 10-14. Measure the pH (pH meter from Dailey TBI, Carson City, NY) use to confirm that you have reached the correct stoichiometry. The above solution is filtered (through a multi-layer plate (plate) Niagra filter from AMETIS, Paoli, PA, and is equipped with a 5-10 micron porous paper from Customs Paper Group, Rochester, MI) in another vessel of stainless steel, of a capacity of 2000 gallons (as described above), and then washed with 275 kg of isopropanol, so as to conserve on the way out. The resulting batch is heated (again using steam with a temperature of 180oFrom entering the tube through the ring of the reactor) to the boiling temperature of phlegmy and approximately 1750 liters azeotrope isopropanol/water is removed by distillation to a final temperature of approximately 83oC. (Azeotrope is condensed in the primary cooler using water at approximately 7oWith, and in the second fridge, using methanol/water "brine" at -35oC). Upon completion of the distillation add 1106 kg of isopropanol to the mixture of product, maintaining the temperature of phlegmy pribliziteljny allocate by centrifugation (using either Tolhurst, or Delaval 48" with a perforated centrifuge drum from AMETEK, Paoli, PA, and the perforated drum, forming at 700-800 rpm, equipped with a fabric having an average porosity of 5-10 microns, from KETEMA, El Cajon, CA), washed with about 50 kg of isopropanol to download centrifuge and dried (at about 60 kPa and 60oWith using vacuum drum dryer for drying haltiwanger from Patterson-Kelly, East Stroudsburq, PA, or using Fitzair the fluidized bed dryer from Fitzpatrick, Elmhurst, IL, and the temperature at the inlet is set at 212oWith the temperature cutoff is set at 225oC). Approximately 700 kg of potassium salt oxaprozin obtained using this procedure.

305,9 kg potassium salt oxaprozin placed in a Niro Fielder PMA 1200 high speed/wysokosciowe granulator (Niro, Inc., above) and stirred for 3 minutes at 70 rpm using a chipping machine at a slow speed. At that time, as there is a stirring, a suspension of 8.4 kg pre gelatinizing corn starch, NF and 68,8 kg of purified water combine in stainless steel tanks for mixing with shirt (Lee Industries Inc., Phillipsburg, PA), mixed at a speed of blades 100% for ten minutes and satelayt slowly, to avoid formation of lumps in the slurry). The warm suspension POPs in the mix potassium salt oxaprozin with pump Graco model # 954-383 with sprayer with #95/10 nozzle (Graco Inc. , Minneapolis, MN). The resulting mixture fray in the wet state using a Quadro Comil Model 198 S mills for grinding in the wet state, equipped with a 1" sieve. The mixture is dried in a fluidized bed dryer (Quadro, Inc., above), equipped with an air stream with a flow rate of 5000 CFM (cubic foot per minute), 37% of the inlet air hole and the air temperature at the inlet 75oC. the moisture Content was approximately 2% (and must be no larger than this value). 1.8 kg of colloidal silicon dioxide, NF is added to this mixture and the resulting mixture is ground using an air jet mill model 007, provided 0,094 sieve at 50% of the screw feed and 60% rotor speed (Quadro, Inc., Millburn, NJ). The mixture is transferred into a cross-flo V mixer (Patterson-Kelly, above) and pre-mixed for 10 minutes. 47,1 kg microcrystalline cellulose, NF, add to the mixture and the mixture is stirred for 10 minutes. 7,2 kg of stearic acid, NF, add to the mixture and the mixture is stirred for 7 minutes.

Received offman Estates, IL), in a way known to specialists in this field. Received tablets containing core, was a white tablet, molded in the form of capsules and the amount of 0,3261" x 0,7480".

Tablets-engine cover film using the aqueous solution of Opadry(Color-con, West Point, PA) at a speed of 400 ml per minute, using Thomas Engineering Accela Cota model 60 DXL machine for applying a film coating (Thomas Engineering, Hoffman Estates, IL), in a way known to specialists in this field. Machine for coating film sets mode: air volume 2600 CFM, speed bowl 4.0 revolutions per minute and the temperature at the inlet 50oWith mechanical movement up and down of the machine for applying film coatings for 3 seconds every 30 seconds. The temperature on the issue, which should never fall below 35oWith support at the 35oC, and the temperature at the entrance, which must not fall below the 43oWith support at the 43oC. the Obtained tablets were painted blue.

As the potassium salt oxaprozin is a photosensitive substance is a chemical substance to protect against excessive exposure to light during the entire process of obtaining described above.

Op is the GLA. 39.

The results of dissolution for this part describes other data on dissolution below in example 5. Experiments on the dissolution is performed by the method described in example 1.

EXAMPLE 3. Sodium salt oxaprozin

A 3-liter, 3-necked round bottom flask equipped with a mixer (all equipment from the supply center of standard laboratory equipment, such as Fisher or Scientific Products), download 293,1 g (1 mol) oxaprozin (Searle Chemical, Augusta, GA) and then 2,05 liters of isopropanol. The resulting mixture was heated to 70o(Using electric heating casing) and then add approximately 495 ml of 2N sodium hydroxide, obtained by dissolving 80,0 g of sodium hydroxide (ACS Reagent Grade, obtained from Aldrich Chemical Co.) in a solution of 15% water/85% methanol, and dilute to volume 1 liter of a solution of 15% water/85% methanol. (The normality of the sodium hydroxide solution confirm with titrimetry).

The above mixture allow to cool to 40oC for one hour. The mixture is cooled to 3oWith using an ice bath, filtered under vacuum on a Buchner funnel fitted with filter paper Whatman #4, washed with twice 100 ml of isopropanol, then dried p is oxaprozin.

Analysis for C18H14NaNO31H2O:

Calculated: 64.88; N, 4.84; N, 4.20; 15.22; Na 7.29 (residue after burning)

Found: 64.97; N, 4.98; N, 4.18; Na 6.88 (residue after burning)

EXAMPLE 4. Tris salt oxaprozin

A 3-liter three-neck round bottom flask equipped with a mixer (all equipment from the supply center of standard laboratory equipment, such as Fisher or Scientific Products), download 366,7 g (1.25 mol) oxaprozin (Searle Chemical, Augusta, GA) and then the solution 154,5 g NHBC (TRIS) in 700 ml of water. The resulting mixture was heated to 60o(Using electric heating casing) and add 1.75 liters of isopropanol. While maintaining a constant volume gradually add 6.5 liters of isopropanol, as the equivalent volume of liquid is distilled off from the system. This way azeotrope to remove water from the vessel. Further mixtures allow to cool to 10oC, then stirred for 30 minutes. The mixture is filtered under vacuum on a Buchner funnel with Whatman paper #4, washed with twice 250 ml of isopropanol and dried at 60oWith in a laboratory dryer with heated air. This procedure gives 499,2 g of Tris salt oxaprozin.

Analysis for C22H26N2O6
I. preparations used in the experiments on the dissolution of the

A. Control structure.

Used control structure was the most preferred composition of the tablets with potassium salt oxaprozin (not containing stearate) (see tab. 40).

C. Test compounds

T-1, T-2, T-3 and T-4 are four different tablets with potassium salt oxaprozin, which differ in the number of stearate used in composition, as shown in the table. 41.

II. Experiments on the dissolution of the

Experiments on the dissolution was carried out by the method described in example 1 to determine the percentage of tablets (control, T-1, T-2, T-3 or T-4), soluble for a specified period of time(10, 15, 20, 30, 45 or 60 minutes), using a wavelength of 286 nm and a concentration of 0.6 mg/ml of Each experiment carried out six times. The data presented in each of these experiments on the dissolution, show the percentage of tablets dissolved at a given time interval.

A. Results for the control sample (without magnesium stearate) (see tab. 42).

Presented in table. 42 data show that approximately 70% of the control tablets (containing no ptx2">

C. Results for sample T-1 (contains 0,244% magnesium stearate) (see tab. 43).

Presented in table. 43 data show that only 37.4% of the tablets T-1 (containing 0,244% stearate) are dissolved in 10 minutes and that the tablet is not completely dissolved after more than 45 minutes.

C. Results for sample 1-2 (contains 0,488% magnesium stearate) (see tab. 44).

Presented in table. 44 data show that only 29.8% of tablets T-2 (containing 0,488% stearate) are dissolved in 10 minutes and that the tablet is not completely dissolved after more than 45 minutes.

D. Results for sample T-3 (contains 0,976% magnesium stearate) (see tab. 45).

The above data show that only 18.6% of the tablets T-3 (containing 0,976% stearate) are dissolved in 10 minutes and that the tablet is not completely dissolved after more than 1 hour.

That is, the Results for sample T-4 (contains 1,952% magnesium stearate) (see tab. 46).

Presented in table. 46 data show that only 15.3% of T-4 tablets (containing 1,952% stearate) are dissolved in 10 minutes and that the tablet is not completely dissolved after more than 1 hour.

EXAMPLE 6. Change active concertacio same wt % of the total mass of the tablet, and then evaluate the dissolution method described in example 1. Each tablet contains ingredients wt % of the total weight of the tablets, which are indicated here below. In table. 47 under the heading "the Total mass of the tablet" presents six tablets of various sizes that contain a specific number of milligrams.

Unless otherwise specified, the tablets used in this study, obtained by the method described in example 2. Tablets are pressed by way of well-known experts in this field, with six different total masses tablets, getting tablets with different active concentrations described below.

Data on dissolution obtained in this experiment are presented in table. 48 and show the percentage of tablets dissolved at different time intervals. Dissolution of tablets was performed by the method described in example 1.

The evidence presented in table. 48 data, all of the above six groups with different weight tablet successfully dissolve in media for dissolution. Although the compositions compacted well and there are no data indicating that adhesion to a mechanical press with increasing total mass of the tablet, you need a higher pressure for the. This is probably irrelevant, since all six types of tablets had acceptable disintegration time (from 7 to 18 minutes). All dissolution tests give acceptable results (average more than 90% in 30 minutes).

EXAMPLE 7. Changes in the concentration of the filler.

In this experiment, the amount of each ingredient tablets-cores with potassium salt oxaprozin described in Example 2, variable, and then conduct the test for dissolution for each of 30 of the obtained compounds. All these structures receive the same manner as described in example 2, and add various fillers at levels specified in the table.49. 30 of the test compounds prepared in small quantities (approximately two pounds).

Data on dissolution obtained from testing these 30 compounds presented in table. 50 shows the percentage of tablets dissolved during different time intervals. The test for dissolution was performed by the method described in example 1.

During this experiment it was observed that tablets, in fact, don't break up, but they apparently poorly erogenous or dissolve.

In addition, during this experiment it was observed that VSTO is tear the side wall and the compositions are more difficult to push out of the mechanical press. This is best seen in the part number 24, where stearic acid was completely removed, and the compositions numbered 22 and 29. To work with the squad number 24 was stopped after it was received enough tablets for testing. The reason is that there were problems associated with the score of the side wall and remove. So we can assume that tested above the formulations of this invention, which contain less than 1% of stearic acid, would be less desirable to obtain tablets on an industrial scale.

EXAMPLE 8. Replacement of the active ingredient

In this experiment, the active ingredient, potassium oxaprozin (potassium salt oxaprozin), replace the two active compounds, sodium oxaprozin and Tris-oxaprozin.

These compounds were obtained in a small amount according to the method described in example 2.

The specific formulations obtained in the experiment presented in table. 51 and 52.

Granulation and molding the tablet with both of the above compositions was successful.

Product with Tris-oxaprozin, apparently, much more soluble than the product with potassium-oxaprozin. This makes the stage of granulation more difficult granulator. This problem is overcome by using the sifting structure through Friewitt vibrazioni granulator (Key International Inc. , Englishtown, NJ) method, well-known experts in this field, before drying in the fluidized bed. In the pressing of tablets, there is some adhesion. This can be corrected by increasing the compression force or some adjustment by adding more lubrication or antiadhesive.

In addition, when the granulation with the sodium oxaprozin required screening when wet and its not so difficult to implement. Also has some wetlands. Test pelletizing with the sodium oxaprozin went well. Mileage tablets went well and there was no sticking at low effort pressing.

The weight of individual tablets was not difficult to control.

Dissolving the above two compositions were tested by the method described in Example 1, and found the percentage of tablets that dissolve at different time intervals. The results of dissolution for both active ingredients-substituents are presented in table. 53. It is seen that more than 95% of the tablets of two different compounds dissolved after 30 minutes.

the om, described in example 2, substitute other fillers from a class with the same function. Classes studied fillers were as follows:

(1) Glidant

(2) Antiadhesive

(3) Binding

(4) Bulking (insoluble and soluble)

(5) Lubrication (water-insoluble and water-soluble)

No other changes in the composition do not.

The results of this experiment are summarized in pairs, as each filler that is present in the product described in example 2, replacing the two alternative fillers of the same class. In all cases, the preparations obtained in this experiment, obtained by the method described in example 2. Data on dissolution obtained from tests of these various drugs that are presented in the various tables below show the percentage of tablets dissolved during different time intervals. The test for dissolution was performed by the method described in example 1.

(1) Glidant

In the first two trials were removed glidant, colloidal silicon dioxide, and replaced it either talcum powder or cornstarch. The preparations obtained in these tests are presented in table. 54 and 55.

Level level is At reception of tablets, when faced with the above criteria, both tests were successful.

When used talc, the weight of the tablets was difficult to control and the flow of the granulate in the car for tabletting, apparently, was difficult. Corn starch were better, and the problems encountered with talc, was not observed (see tab. 56).

The results of testing the dissolution showed that the replacement of colloidal silicon dioxide, talc or corn starch does not impact adversely on the dissolution rate. Experiments on the dissolution of each of these compounds showed that more than 98% of the tablets dissolve over a thirty minute interval.

(2) Antiadhesive

In two trials of the second pair remove release agent, colloidal silicon dioxide, and replace it or stearate, or valium. The compositions obtained in these tests are presented in table. 57 and 58..

In both cases, the content of antiadhesive was 0.5% wt/wt (0.5% of the total mass of the tablet). No problems that prevented any of these tests, the weight of tablets was easy to control and the flow of the granulate in the car for tableting was good. No pokazateli demonstrate what the above substitution does not affect adversely on the dissolution. Experiments on the dissolution of each of these compounds showed almost 100% dissolution of tablets for the thirty-minute time interval.

(3) Binding

In two trials of the third pair remove the binder is corn starch, and replace it with either sucrose or polyvinylpyrrolidone (PVP, PVP). The compositions obtained in these tests are presented in table. 60 and 61.

The level of sucrose was 3.8% wt/wt (3.8% of the total weight of the tablet) and the level PVP was 2.0% wt/wt (2% of the total mass of the tablet). As for both tests, the experiments on granulation went well, masses for tablets and the flow of the composition through the machine for tableting were good, and there was no evidence of adhesion (see tab. 62)

The results of testing the dissolution showed that replacing corn starch or PVP, or sucrose does not adversely affect the dissolution. Values for dissolving tablets for thirty minute interval for both replacements exceeded 97,0%.

(4) Fillers

(a) water-Insoluble fillers

In two trials the fourth pair remove water-insoluble filler - microcrys storytime fillers. The compositions obtained in these tests are presented in table. 63 and 64.

In each case, the replacement was 1:1 (use the same number of mg of water-insoluble filler). Each part can be easily pressed in the press for tableting, and there was no evidence of sticking in the press (see tab. 65).

The results of testing the dissolution showed that when replacing microcrystalline cellulose, or dicalcium phosphate or calcium carbonate, is not observed according to the above criteria.

(b) a water-Soluble fillers

In two trials the fifth pair remove water-insoluble filler is microcrystalline cellulose and replaced it with either sucrose or lactose, both of which are water-soluble fillers. The compositions obtained in these tests are presented in table. 66 and 67.

In both cases, the replacement was 1:1. Tablets were easily merged in the press for tableting, and appearance each of the two series of tablets has been improved due to the apparent brilliance. Mass for tablets and for trains through the machine for tableting were good, and there was no evidence of sticking of the tablets in the press for tabletterbinafine increases for both types of replacement. The percentage of tablets dissolved at thirty minute intervals for each type of replacement was more than 99,5%.

(6) Toll substances

A study in the part, where they spent an oil change, consisted of four trials. In all cases the tests were carried out with compositions in which stearic acid was removed and replaced with either water-insoluble or water-soluble lubricant.

(a) water-Insoluble lubricants

In the first test on the replacement of water-insoluble lubricants remove stearic acid and replace it with calcium stearate - water-insoluble lubricant. The preparation obtained in this trial are presented in table. 69.

Although this composition was obtained enough tablets for this experiment, there was a tear of the lateral walls (problems with removing the head (molds) of the machine for pressing tablets). To avoid damage to the machine for tabletting, only 230 g of the composition was compressed into tablets. The level of calcium stearate was 0.5% wt/wt (0.5% of the total weight of the tablet).

In the second case, the test for the replacement of the water-insoluble lubricants remove stearic KIS is pytanie, presented in table. 70.

This test was stopped due to adhesion of the granules to the top and bottom surfaces of the punches teletrauma machine. The level of hydrogenated castor oil was 2.0% wt/wt (2% by weight of the total tablet). To improve the results of this test in this structure add additional grease (water-insoluble) and 2.0% wt/wt of glyceraldehyde (Gattefosse, St. Priest, France). This composition resulted in excessive adhesion in the car for tableting. So with this composition were tested for dissolution.

In the third case, in the test with the replacement of the water-insoluble lubricant, remove the stearic acid and replace its water-insoluble lubricant, talc. The preparation obtained in this trial are presented in table. 71.

The level used talc was 4.8% wt/wt (4.8% of the total weight of the tablet). In this test, to control the weight of tablets was easy. There was some sticking to the surfaces of the punch machine for tabletting, but only as the result of granulation on the surface of the punch is formed waxy film, which had a tendency to stick to the surfaces of the punch, the adhesion was not aggravated by the s, obtained by replacing the water-insoluble grease calcium stearate and talc, more than 96% of tablets containing these two drugs are dissolved in thirty minutes. Due to difficulties in pelletizing experienced with the composition obtained with calcium stearate, the use of talc in the composition of this invention preferably compared with the use of calcium stearate.

(b) a water-Soluble lubricants

In the final three experiments on replacement remove stearic acid, and replaced it with a water-soluble lubricating substances.

In the first experiment stearic acid is removed and replaced her by sodium dodecyl sulfate at a level of 4.0% wt/wt (4.0 percent by weight of the tablet). The preparation obtained in this trial are presented in table. 73.

In the originally received the tablets have got dents due to damage to the workpiece in the machine punches for tabletting, but this adhesion stopped, if occurred, with increasing pressing force used in the car for tableting.

In the following experiment by replacing stearic acid is removed and replaced it with a water-soluble lubricant, polyethylene-glycol (PEG) 4600. Drug, sex is m punch machine for tableting. To reduce this adhesive composition to add the polyethylene glycol 8000. The levels of both test glycols amounted to 4.0% wt/wt (4% by weight of the tablet). Because of the same problem with this experiment was terminated, and experiments on the dissolution of this composition was not performed.

In the final experiment on replacement remove stearic acid, and replaced it with water-soluble lubricant is sodium fumarate. The preparation obtained in this trial are presented in table. 75.

The level of sodium fumarate was 2.0% wt/wt (2% by weight of the tablet). Force pressing in the car for tabletting should be slightly increased in order to avoid sticking, but the mass of the tablets and the flow of the composition through the machine good (see tab. 76).

The results of dissolution tests showed that the replacement of sodium laurylsulfate and sodium fumarate increase the dissolution (tablets). Both experiments for the replacement show that more than 99.9% of tablets made from these compounds, dissolved in thirty minute intervals.

EXAMPLE 10. Remove filler

In this experiment, prepare tablets, using only potassium oxaprozin.

The pills were small variations in the mass and well kept thickness. Strength was very low (average 1.3 KS (Kr)). Time raspadaemosti was very small (4 to 5 minutes) (see table. 77).

The conclusion that can be drawn from this experiment is that the composition of the tablets, which use only the active potassium oxaprozin, leads to the formation of tablets with an acceptable dissolution profile.

EXAMPLE 11. Define maximum number of stearic to the which you can use as a lubricant in the preparation oxaprozin potassium, without adverse effects on dissolution.

The maximum number of stearic acid, which can be used in the preparation containing potassium oxaprozin, was determined as follows. A small batch was mixed in a V-mixer and then extruded on a rotary press for tableting. The obtained tablets were tested on raspadaemost, and time raspadaemosti used as an indicator of whether tablets undergo dissolution. The only difference in the preparations consisted in the fact that the compositions contained a different percentage of stearic acid. The levels used stearic acid were: 5.7, 10, 15, 17.5 and 20% wt/wt. The actual compositions are presented in table. 78.

From time raspadaemosti for different formulations, preparations with a content of 17.5% and 20% of stearic acid were transferred to the laboratory for testing dissolution (see tab. 79 and 80).

The conclusion that can be drawn from the above experiment, is that the maximum amount of stearic acid, which can be used in the composition of the tablets with an acceptable dissolution profile, a little more than 17.5%, but less than 20,0%.

EXAMPLE 12. Experiments on opredelennnogo the number of pre-gelatinizing corn starch, which can be used as a binder in the current structure for oxaprozin potassium, without adverse effects on dissolution.

All tests are performed in the same manner using the same equipment. Ingredients granularit in Fuji vertical granulator, dried in an oven with forced air flow and tabletirujut on a Kilian rotary press for tableting. The only difference was the percentage of starch that is used in each of the compositions. Levels pre-gelatinizing corn starch was 5, 10, 12.5, 15 and 30% wt/wt.

After the tablets were pressed, they were transferred to the laboratory for testing dissolution.

The individual compositions are presented in table. 81 and 82.

The results of dissolution tests show that the level of pre-gelatinizing corn starch, even at 30%, has no adverse effect on the dissolution. On this basis, it is possible to predict that you can use any level of pre-gelatinizing starch and that, most likely, it will not affect dissolution.

The preceding examples is Auda merely illustrative and should not be considered, as limiting the scope of the invention claimed in the following claims.

(7) a Description of clinical trials

A. Research biodiscovery

Studies on pharmacokinetics, clinical bioavailability of the composition of the potassium salt oxaprozin described in example 2, described below, and here presented studies with single and multiple dose, which compare the concentrations of total and unbound oxaprozin in plasma obtained from Daypro(acid form oxaprozin) and potassium salt oxaprozin described in example 2.

A study with a single dose

It was conducted-day, open, randomized, parallel study with a single dose of 36 healthy objects (12 per treatment), aged 19-44 years (27 males and 9 females), at Evanston Hospital in Evanston, Illinois in March and April 1995, with the aim to evaluate the absorption rate (how fast it comes from the stomach into the systemic circulation, in terms of Cmax) and bioavailability (percent composition, which becomes absorbed from the gastrointestinal tract) oxaprozin have been subjected to fasting subjects from a single 1200 mg oral dose (two 600 mg cabledata; and (3) composition 100% potassium salt oxaprozin described in example 2. Patients each received one single dose of one of these three compositions. Blood samples for analysis oxaprozin were collected at pre-set intervals over a period of ten days after dosing. Parameters oxaprozin in plasma that were evaluated were AUC, AUC0-Cmax, Tmax, MRT and T1/2as for unrelated oxaprozin and total oxaprozin (unbound oxa-prosin plus oxaprozin associated plasma protein-albumin). (NSAID's, as a class, shows strong binding to plasma protein, mainly albumin).

Were built based concentrations in plasma both in total and unbound oxaprozin over time for each subject. In addition, the dependences of the average value of the concentrations in plasma total and unbound oxaprozin over time for each group subjected to processing.

From each curve of the plasma concentration/time were calculated shown below pharmacokinetic parameters for total and unbound oxaprozin:

oWITHmaxthe maximum observed total concentration>/BR>oAUC(O-t)the area under the curve "concentration oxaprozin plasma-time" determined using the linear trapezoidal method:

< / BR>
where T=240 hours for total and 48 hours for unrelated oxaprozin,irepresents the concentration oxaprozin the i-th plasma samples, tirepresents the current time of the i-th plasma samples, and n represents the number containing the (non-missing) oxaprozin samples up to T hours after treatment;

AUC(0-)the area under the curve "concentration oxaprozin plasma-time, from time = 0 to infinity, calculated as follows:

< / BR>
where TLQCrepresents the time, which was determined quantitatively last concentration, LQC is the last quantifiable concentration oxaprozin in plasma and denotes the rate constant for the final removal set as the negative logethe slope of a simple linear regression (concentration oxaprozin plasma) depending on time (number of time points used in regresi, determined after analysis of the shape of the curve "concentration oxaprozin plasma-time");

MRT(0-)average time Eledoisin follows:

< / BR>
where AUMC(0-)denotes the area under the curve graph of the dependence of the concentration of the product oxaprozin in plasma from time to time and from 0 to infinity, known as the area under the curve (first) moment and is calculated as follows:

< / BR>
< / BR>
oT1/2: half-life (final removal from the body) (terminal elimination half life) for levels oxaprozin in the plasma, calculated as

T1/2=loge2/.

As for total and unbound oxaprozin compared the following pharmacokinetic parameters for the three groups: AUC, MRT,maxTmaxand T1/2. In these comparisons acid oxaprozin designated as part of the comparison, and the other two composition as the test compounds. AUC, MRT and Cmaxwere transformed into logeprior to analysis. For each logerasformirovannoj parameter 90% confidence interval calculated for the difference (test-comparison between arithmetic mean. The end point of this interval is expressed as an Exhibitor, to get an approximate 90% confidence interval for the relationship of the respective geometric means (test/comparison).

The results of this study in relation to the CLASS="ptx2">

Compared with Dayprocomposition with 100% salt shows a much higher rate of absorption. Peak concentrations in plasma (Cmaxtotal and unbound oxaprozin in the processing of 100% potassium salt oxaprozin increase by 26% and 49%, respectively. Plasma concentrations with the composition of the salt is less variable [AUC (0-240) for the summary of the medicinal product: CV= 14% (Sol) compared with 26% (Daypro)]. This means that the concentration in the plasma drug patients should be more predictable for patients who take part potassium salt oxaprozin than for patients who are taking Daypro.

Study with multiple doses

There was an open, randomized, parallel study with multiple doses of 40 (36 completed the study) healthy subjects (12 per treatment) to assess the bioavailability of total and unbound oxaprozin from taking multiple 1200 mg doses oxaprozin given once daily for eight days in the form of tablets acid oxaprozin (Daypro), a mixture of 60%/40% salt/acid or 100% potassium salt oxaprozin, composition described in example 2. Concentration summarv) from blood samples, taken at different time intervals throughout a 24-hour period after administration of doses on days 1, 5 and 8, and from the samples prior to dose (pre-dose samples, predose (trough)) taken on days 3, 4 and 7.

Build a graph of concentrations of total and unbound oxaprozin in plasma over time for each subject for days 1, 5 and 8 of the study. In addition, build a graph of average concentrations of total and unbound oxaprozin in plasma over time for each group to be processed. Concentrations of total and unbound oxaprozin summarize each point in time during treatment.

From each curve "concentration-time" count below pharmacokinetic parameters for total and unbound oxaprozin on the days of study 1, 5 and 8:

oCmax: maximum observed total concentration oxaprozin,

oCmin: pre-dose concentration oxaprozin plasma,

oTmax: the time during which there is the maximum concentration of total oxaprozin, and

oAUC(0-24): area under the curve "concentration oxaprozin plasma-time", installed with the use of the i-th plasma sample, tiindicates the current time of the i-th plasma samples and n represents the number containing the (non-missing) oxaprozin samples up to 24 after processing.

In addition, on the days of study 5 and 8, for both the total and the associated oxaprozin, calculate the following pharmacokinetic parameters:

(Cmax-Cmin)/Cmin< / BR>
If the value on study day 1 were absent, for the calculation of pharmacokinetic parameters using a value of zero. If the value in the pre-dose plasma was absent on study day 5 or day of the study 8, the calculation of pharmacokinetic parameters taken pre-dose value in the plasma prior to the day of the study.

Pharmacokinetic parameters for total and unbound oxaprozin, summarize for the three treatment groups for days study 1, 5 and 8, using standard statistics summation AUC, CmaxWITHminand Tmax.

Relations AUC on study day 8 to AUC on study day 1 compared for the three groups using non-multiple analysis of model differences, for both total and unbound oxaprozin. Relationships transform into the log until analysis.

Within each treatment was slevel for ratio values:

AUC, CmaxCmin, Tmaxand (Cmax-Cmin)/Smin.

In each of these comparisons study day 5 is designated as the comparison and study day 8 is designated as the test.

Comparison between treatments performed for AUC, Cmaxand Tmaxon study day 1 and AUC, WITHmaxWITHminTmaxand (Cmax-Cmin)/Cminon study day 8, using 90% confidence interval for ratio values. These comparisons are conducted for 100% of salt oxaprozin (test) relative to 100% acid oxaprozin (comparison) and for 60% of salt oxaprozin/40% acid (test) relative to 100% acid oxaprozin (comparison). Within-treatment and between-treatment comparisons, AUC,maxand (Cmax-Cmin)/Cminconvert log in to the analysis. For each log transformed parameter 90% confidence interval calculated for the difference (test-comparison between arithmetic averages. The end point of this interval is converted into the Exhibitor to obtain approximate 90% confidence interval for the relationship of the respective geometric means (test/comparison).

For the untransformed parameters each 90% confidence INTUITY (test-comparison between arithmetic averages. The desired approximate 90% confidence interval for the arithmetic average is the quotient of the end points of this interval on the arithmetic mean of the comparison and add 1 to each result.

The parameters obtained from the different composition or different days of the study), are considered equivalent if the calculated 90% confidence interval is completely contained within (0.8, 1.25) for the converted log inethe parameters and in (0.8, 1.2) for the untransformed parameters.

The results of the study with multiple doses are summarized in Table 2A. Comparison of stationary pharmacokinetic parameters, either for total or unbound oxa-prozine with Dayproand with the composition of the potassium salt oxaprozin described in example 2 gave similar results when used values of concentrations of either day 5 or day 8. For this reason, this discussion presents data only for day 5.

In addition, in the steady state is visible, the smaller the variability between subjects in the concentrations of the composition of the potassium salt oxaprozin in the plasma of subjects when compared with Dayprosubjects [CV for AUC (0-24) total oxaprozin = 15% (Sol) Ino Dayprosalt gives 12% and 4% increase FROMmaxand AUC (0-24), respectively, for a total medicines. For unbound drug has a 23% increase in inmaxand there is no increase in AUC (0-24) (table 2A).

Results

The above results on the investigation of bioavailability of single dose and multiple dose demonstrate the following:

(1) In the case of the composition of the potassium salt oxaprozin described in example 2, the speed of absorption oxaprozin higher and less variable than in the case of tablets Daypro.

(2) After enter is equivalent to 1200 mg dose in the form of Dayproor composition of the potassium salt oxaprozin, the duration of total or free oxaprozin in a stationary state in the case of salts does not exceed the duration of total or free oxaprozin in the case of acid oxaprozin more than 10%.

(3) the composition of the potassium salt oxaprozin demonstrates less variability than Dayproor tablets with a combination of salt/acid.

(C) the Study of analgesia

Assessment was conducted for the two compounds with potassium salt oxaprozin in the once-blind, PLA is tological surgery, resulting from the removal of teeth. Be evaluated two groups represented the composition of 100% potassium salt oxaprozin described in example 2, and a combination tablet containing the same ingredients, and the percentage of them, except that as the active ingredient was used a combination of 60% potassium oxaprozin and 40% oxaprozin acid. Dayproincluded in this study as a comparative product. Nuprin (Nuprin) (Ibuprofen, Bristol-Myers, New York, NY) included in this study as a positive control and placebo included in this study as a negative control. The purpose of the study is to obtain data on analgesia for two formulations of potassium.

The study was planned experiment with once-blind, single dose, parallel groups, in which 282 patients were randomly divided into the following five groups subject to treatment:

(1) Daypro/single dose of 1200 mg (two 600 mg-type tablets) - 57 patients

(2) Composition 100% potassium salt oxaprozin described in example 2, a single dose of 1200 mg (two 600 mg-type tablets) - 58 patients

(3) Oxaprozin potassium/oxaprozin acid 60%/40% combination, R. and) - 56 patients

(5) Placebo (2 tablets) of 55 patients.

Were measured and compared these different variables reflecting efficiency:

(1) the difference in the intensity of pain (PID), using the classification scale (Tables 1 and 2) and VAS (visual analogue scale (visual analog scale)) (Tables 3 and 4) ;

(2) the decrease in pain was assessed using a classification scale (Table 5 and 6);

(3) classified the pain and the measurement of the combination of the difference in the intensity of pain (Tables 7 and 8); and

(4) the percentage of patients who experienced a 50% decrease in pain (Tables 9 and 10).

All variables assessed at baseline (time directly before taking the medicinal product to be tested, and which corresponds to the time after which the patient felt severe to moderate pain), and when the time 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours. Visual analogue scale expresses the magnitude of pain in mm printed on a 100 mm line, which extends from the lack of pain in 0 mm to the most severe pain when 100 mm Classification scale expresses the difference in pain intensity (PID) as an expense on a 4-point scale, which is the following:

0=no, 1=weak, 2=mind the different variables, characterizing efficiency, are presented in Tables 1-10 below.

In tables 1-4, the difference in pain intensity (PID) is measured by the change in pain from baseline. Its calculated as follows: (Baseline pain score) minus (the pain score at Time N). Positive values indicate a decrease in pain (the pain from the baseline). SPID1 represents the amount of difference in the intensity of pain each patient at time 0.25, 0.50, 0.75 and 1.00 hour. Tmax(PID) refers to the time when the difference in the intensity of pain (PID) patient reaches its maximum value (maximum pain) over 8-hour interval of time.

In Tables 5 and 6 scale relief of pain expresses the pain, as the score on a 4-point scale, which is the following: 0=no, 1=little, 2=some, 3=a lot more, 4=complete. Scores of pain used to calculate values of pain each time. The higher the value, the better the pain. TOTPAR1 represents the sum of accounts relieve the pain of each patient at time 0.25, 0.50, 0.75 and 1.00 hour. Tmax(R) means the time when the expense of weakening the pain reaches the maximum value within an 8-hour interval of time.

In tables 9 and 10 the number of hours with 50% pain reduction is calculated as the sum of all time intervals, where the patient has experienced a 50% decrease in pain. The sensitivity threshold (censoring value (the standard number used for inclusion in the equation for patients who have not experienced a 50% decrease in pain for 3 hours and takes relieve pain (deblocare) drug) is equal to 8.1. (Debateroom drug is any downward pain medication, such as ibuprofen or vicodin)"****" indicates the time when the patient experienced at least a 50% decrease in pain for more than 8 hours. 95% confidence interval for the average calculated using the nonparametric sign test (nonparametric sign test), as described R. Brookmeyer et al., "A Confidence Interval for the Median Survival Time", Biometrics, 38, 29-41 (1982), which is included for information.

In table 10 the P-Value (probability of statistical significance between tatements (standard statistical computer programs, well-known experts in this field, which is available from SAS Institute, Inc., Saga, NC, and are given for information). P-Values in regard to the first time 50% relief of pain (the first time 50% pain relief) were obtained from the LOC RANK test, which is described in R. G. Miller, Survival Analisis (John Wiley & Sons, New York, NY, 1981), which is included for information.

Tablet 100% oxaprozin potassium, described in example 2, demonstrates a statistically significantly faster onset of action than acid oxaprozin, and numerically better than the tablet based on the combination of oxaprozin potassium/oxaprozin acid for each parameter efficiency.

No statistically significant difference for PID measurements within the first hour (P0,055) between oxaprozin potassium and oxaprozin acid or oxaprozin potassium and combination oxaprozin potassium/oxaprozin acid. However, there are statistically significant differences between the composition of the potassium salt oxaprozin described in example 2, compared with Dayprowithin the first hour accounts for the relief of pain (starting at 0.5 hours, the probability (p)= 0,017), the amount of difference in the intensity of pain and relief of pain (starting at 0.5 hours (p=0,042) and the percentage of patients experiencing at least 5 is salsa most effective taking into account the effect during the first hour, and time to maximum values for the variables characterizing the efficiency.

Conclusions

The composition of the potassium salt oxaprozin described in example 2, provides a statistically significantly faster onset of action compared with Daypromoreover , the difference occurs in the time interval from 0.5 to 0.75 hours after dosing. In addition, the composition of the potassium salt oxaprozin described in Example 2, numerically better than the combination of oxaprozin potassium/oxaprozin acid in all parameters characterizing the efficiency, within the first hour after dosing. (The beginning of the analgesic action is defined as the time when the effectiveness of the composition of the potassium salt oxaprozin becomes significantly different from placebo, and this occurs within up to 1 hour after the time of injection).

Although this invention has been described quite specifically and referring to some preferred variants of its realization, for specialists in this area it is obvious that various changes, modifications and substitutions to the fact that it is described that can be made and which are not beyond obadoni, presented in the description, as a consequence of changes in the sensitivity of the animal to be treated, the harmful effects associated with the dosing, if at all required, and similar considerations. Similarly, specific observable pharmacological responses can vary according to, depending on the specific active ingredient, or if there are certain pharmaceutical carriers, as well as the type of composition used and route of administration. Such expected changes and/or differences in the results are expected to be in line with the objectives and practical implementation of this invention. Therefore, it is implied that all these modifications and changes are within the scope of the present invention described herein and claimed in the claims and that the invention is limited only by the amount of the following claims and that such claims be interpreted as broadly as is reasonable.

Within any component of the drug can be classified in more than one of the classes of components, the amount of such a component in the unit is within range of such a component, as described the Oia in solid dosage form, comprising as an active agent potassium, sodium or Tris salt oxaprozin, and specified the pharmaceutical composition contains less than 1% of magnesium stearate, and about 75% of the active agent specified dosage form dissolved in 1000 ml phosphate buffer pH 7.4, at 37oWith under stirring paddle stirrer with a speed of 75 rpm. /min for about 30 minutes

2. The pharmaceutical composition under item 1, characterized in that the active agent is a potassium salt oxaprozin.

3. The pharmaceutical composition under item 1, characterized in that the active agent is a sodium salt oxaprozin.

4. The pharmaceutical composition under item 1, characterized in that the active agent is Tris salt oxaprozin.

5. The pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that it contains from 37,14 to 100% of the active agent to the total weight of the composition.

6. The pharmaceutical composition under item 1, characterized in that it further contains less than 2 weight. % methylcellulose.

7. The pharmaceutical composition under item 1, characterized in that the said composition is essentially free of metallic stearates.

8. Pharmaceutical composition for p. farmacevticheskaja composition in solid dosage form, comprising as an active agent potassium, sodium or Tris salt oxaprozin and lubricating substance selected from the group consisting of water-insoluble lubricants and water-soluble lubricants, with approximately 75% of the active agent specified solid dosage form dissolved in 1000 ml of phosphate buffer with pH 7.4, at 37oC, under stirring paddle stirrer with a speed of 75 rpm. rpm, for about 30 minutes

10. The pharmaceutical composition according to p. 9, characterized in that it contains an active agent in an amount of from 37,14 to about 100% of the total weight of the composition.

11. The pharmaceutical composition according to p. 9, characterized in that it contains a lubricating substance in an amount of from about 0.25 to about 20% of the total weight of the composition.

12. The pharmaceutical composition according to p. 9, characterized in that it contains less than 1 weight. % of magnesium stearate.

13. The pharmaceutical composition according to p. 9, characterized in that it is essentially free of metallic stearates.

14. The pharmaceutical composition according to p. 9, characterized in that it contains less than 2 weight. % methylcellulose.

15. The pharmaceutical composition according to p. 11, wherein the solid drug is the lasting themes that water-insoluble lubricating substance selected from the group consisting of calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil and talc.

17. The pharmaceutical composition according to p. 9, wherein the water-soluble binder is sodium lauryl sulphate or sodium stearyl fumarate.

18. The pharmaceutical composition according to p. 9, characterized in that it further includes a binding agent.

19. The pharmaceutical composition under item 18, characterized in that it includes from about 0.25 to about 30% binder by weight of the composition.

20. The pharmaceutical composition according to p. 19, wherein the binder is selected from the group consisting of corn starch, pre-gelatinizing starch, sucrose, polyvinylpyrrolidone, methyl cellulose, sodium carboxymethyl cellulose and ethyl cellulose.

21. The pharmaceutical composition under item 18, characterized in that it further includes a filler.

22. The pharmaceutical composition according to p. 21, characterized in that said filler is microcrystalline cellulose.

23. Pharmaceutical composition in the TV the NTA in the amount of from about 70 to about 90% by weight of the composition, stearic acid in amounts of from about 1 to about 4% by weight of the composition, pre-gelatinizing starch in an amount of from about 0.25 to about 25% by weight of the composition, and optionally microcrystalline cellulose in an amount of from about 0 to about 27% by weight of the composition, with 75% of the active agent specified solid dosage form is dissolved in 1000 ml phosphate buffer pH 7.4, at 37oC, under stirring paddle stirrer with a speed of 75 rpm. rpm, for about 30 minutes

24. Pharmaceutical composition for p. 23, characterized in that said active agent is a potassium salt oxaprozin.

25. The pharmaceutical composition according to p. 24, characterized in that it comprises microcrystalline cellulose.

26. Pharmaceutical composition for p. 23, characterized in that it comprises less than 1 weight. % of magnesium stearate.

27. Pharmaceutical composition for p. 23, characterized in that the essentially free of metallic stearates.

28. Pharmaceutical composition for p. 23, characterized in that it contains less than 2% methylcellulose.

29. The pharmaceutical composition according to any one of paragraphs. 1, 9 or 23, characterized in that about 95% of the active agent specified solid is a mini-composition in solid dosage form for eliminating or reducing pain in a mammal, in need of such treatment, comprising an effective amount of potassium, sodium or Tris salt oxaprozin as the active agent, and about 75% of the active agent dissolved in 1000 ml phosphate buffer pH 7.4, at 37oC, under stirring paddle stirrer with a speed of 75 rpm. /min for 30 minutes

31. The pharmaceutical composition according to p. 30, characterized in that it includes from about 37,14 to about 100% of the active agent to the total weight of the composition.

32. The pharmaceutical composition according to p. 30, wherein the solid dosage form is a tablet, pill or Capitol.

33. Pharmaceutical composition for treating inflammation or inflammation-related disorders in a mammal in need of such treatment, comprising an effective amount of potassium, sodium or Tris salt oxaprozin as the active agent.

34. Pharmaceutical composition for p. 33, characterized in that it contains from about 37,14 to about 100% of the active agent to the total weight of the composition.

35. Pharmaceutical composition for p. 33, wherein the solid dosage form is a tablet, pill or caplet.

36. Pharmaceutical compositions which I specified in phosphate buffer for 30 minutes

 

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