HU201875B - Process for producing retarde pharmaceutical compositions containing acetyl-salicylic acid - Google Patents

Description

The present invention relates to pharmaceutical compositions for sustained release of acetylsalicylic acid.

Surprisingly, it has been found that a readily available and sustained release (hereinafter "sustained release") dosage form can be prepared with readily available and generally approved microcrystalline cellulose and hydroxypropyl methylcellulose as carriers.

Pharmaceutical compositions containing microcrystalline cellulose are described in Indian Drugs 21, 201-205 (1984); No. 4,520,009 U.S. Pat. Chem. Pharm. Bull. 34, 850-857 (1986).

Pharmaceutical compositions containing hydroxypropyl methylcellulose are disclosed in U.S. Patent No. 2,010,115. German Patent Publication No. 4,302,440; U.S. Pat.

Pharmazie discloses a tablet containing acetylsalicylic acid (33, 747-749 (1978)), which uses microcrystalline cellulose as an excipient and hydroxypropyl cellulose as a tablet for wet granulation.

To date, no pharmaceutical formulation containing microcrystalline cellulose and hydroxypropylmethyl cellulose at the same time as a sustained release excipient has been known. FIELD OF THE INVENTION The present invention relates to a process for preparing a sustained release pharmaceutical composition comprising acetylsalicylic acid (hereinafter ASA) in combination with a) microcrystalline cellulose and b) hydroxypropyl) methylcellulose, wherein the ratio of component a) to component b) is at least 1%. : first This pharmaceutical composition is prepared according to the invention by mixing acetylsalicylic acid with (a) microcrystalline cellulose and (b) hydroxypropylmethylcellulose in a ratio of at least 1: 1 by weight relative to component (b).

The ASA is preferably used in the form of the free acid; however, it may also be present in the form of a salt such as a sodium or calcium salt. Preferably, ASA is used in a fine crystalline form, such as a particle size of 0.4 to 4 mm.

The average degree of polymerization of the microcrystalline cellulose used in the process of the present invention ranges from about 200 to about 2000, preferably from about 200 to about 300; The average molecular weight is preferably from about 20,000 to about 100,000, for example from 30,000 to 50,000. Preferably, it has a density of about 1.40 to about 1.60. Microcrystalline cellulose is conveniently prepared by mechanical treatment, optionally with acid treatment, of glucose-based polysaccharides, such as natural cellulose. Avicel ^R (trademarked by FMC Corporation, Marcus Hook, USA) is preferred.

The methoxy content of hydroxypropylmethylcellulose is preferably about 15-34% by weight, preferably about 19-30, especially 19-24% by weight; (hydroxypropyl) preferably contains from about 4% to about 32% by weight, preferably from 4% to 12% by weight.

The viscosity of hydroxypropyl methylcellulose is preferably about 15-50,000 cps (based on a 2% w / w aqueous solution at 20 ° C), for example 4-50 Pa.s. The average molecular weight is suitably about 20,000-20,000, for example 90,000-130,000.

Hydroxypropyl methylcellulose is conveniently available as Methocel A, K and E under the trade names (Dow Chemical Company, Michigan, USA).

The weight ratio of microcrystalline cellulose to hydroxypropyl methylcellulose is preferably from about 10: 1 to 1: 1, such as from 3: 1 to 1: 1, for example from 3: 1 to 2: 1. .

The weight ratio of microcrystalline cellulose to active ingredient ranges from 1: 5 to 1: 10, for example from 1: 6 to 1: 7.5, in particular from 1: 6.5 to 1: 7. Pre-gelatinized starch is preferably used in the composition. The starch is preferably soluble in about 5 to 25, for example 10 to 25% by weight of cold water. Pre-gelatinized starch is preferably prepared by treating the starch, preferably cereal starch (containing 80% amylopectin moiety and 20% amylase moiety) such that the hydrogen bonds between amylose and amylopectin are broken. The product preferably contains from 60% to 85% by weight of cereal starch, the remainder being free amylose and amylopectin.

The weight ratio of pregelatinized starch to hydroxypropyl methylcellulose ranges from about 1: 1 to about 1: 5, for example from about 1: 1 to about 1: 2.

Of course, other excipients may be present in the formulation. These carriers include those commonly used in pharmaceutical formulations, such as friction reducing agents such as stearic acid or magnesium stearate, and lubricating agents such as silicon dioxide, and adhesives, soluble fillers such as lactose, and flavorings and colorings.

The weight ratio of active ingredient to all other carriers is preferably from about 0.2: 1 to about 0.4-1, for example from about 2: 1 to about 4: 1. Hydroxypropyl methylcellulose is present in an amount of about 5 to 10% by weight, for example 69%, especially 6.5 or 8.5% by weight.

The pharmaceutical composition according to the invention is preferably in solid form and preferably in unit dosage form, preferably in tablet form.

ASA is conveniently administered in an amount of 300400 mg or 600-700 mg per dosage unit. Such pharmaceutical compositions may be prepared by well-known methods.

Tablets are preferably made with a hardness of about 8-12 kiloponds (according to the Heberlein method).

The bioavailability of the compositions of the invention is determined in the usual manner.

In a typical experiment, an ASA-containing pharmaceutical composition of the present invention is administered at 7 am and then at 3 pm and 11 pm; or 7am and 7pm. The reference formulation is direct drug kbo-21

HU 201875 Β cadaveric ASA preparations are administered at 7 am, then at 11, 15, 19 and 23.

The amount of free and total salicylic acid (hereinafter referred to as "SA") is determined by conventional high performance liquid chromatography (HPLC) [essentially the method of Hamson et al., J. Pharm. Sci., 69, 1268 (1980)].

Method for the determination of free Sa

Heparinized blood samples are collected; within 15 minutes of receiving the blood sample, the plasma is separated, divided into two portions and placed in polypropylene tubes, which are closed with color-coded polypropylene plugs.

A 0.5 ml sample was acidified with 1 drop of concentrated phosphoric acid and after a few minutes extracted with a 50:50 mixture of toluene and ethyl acetate. The extract was analyzed by reverse phase HPLC and detected by UV at 305 nm with an internal standard of 3,4-dimethoxybenzoic acid. By this method, the minimum detectable amount is 0.1 microgram / ml free SA.

Methods for determining all SAs

Total SA is determined in the urine as salicylic acid. A volume of 1 ml of urine was mixed with 1 ml of concentrated hydrochloric acid, sealed and heated at 98 ° C for 16 hours, then allowed to cool and 1 ml of acetonitrile containing the internal standard was added. The samples were then subjected to HPLC analysis and SA was detected by UV spectroscopy at 313 nm.

The bioavailability test is preferably conducted for at least 8 days. Further details emerge from the experiments described below. The average salicylate concentrations measured indicate that the bioavailability of free salicylate in the blood resulting from the pharmaceutical composition of the present invention is unexpectedly high, especially with respect to the anti-inflammatory therapeutic level.

The experiments described below show that the kinetics of ASA are non-linear as the area under the 0-8 hour curve (AUC) for free salicylate is disproportionately affected by administration of 3.9 g ASA (i.e., 3x1300 mg ASA daily in Experiment A). greater than 2.6 g ASA (i.e. 2x1300 mg ASA daily in Experiment B). Urinary excretion data show that cumulative excretion of all SAs is similar and dose independent for administration of 2.6 g ASA and 3.9 g ASA.

These results suggest that at high doses of ASA that induce anti-inflammatory activity, the metabolic pathways are permanently saturated (indicated by dose-independent cumulative values in urinary excretion). Plasma concentrations of free SA were found to increase disproportionately with increasing dose at high ASA doses. In our view, this fact is attributable to the combined clearance effect of unbound ASA and the ratio of plasma-bound protein-bound SA to unbound Sa. If the metabolism is saturable, the clearance should decrease, but if the protein binding is saturated, the clearance will increase. As a result, the steady state concentration of free SA may depend on the magnitude of any of these two effects.

The pharmaceutical formulations of the present invention have a longer elimination half-life (e.g., greater than 9 hours) than the pharmaceutical formulations that directly release ASA. In the case of direct release ASA formulations, the ratio of the peak of free SA to the nadir can be high and consequently, periods of enhanced metabolism occur, resulting in low SA concentrations. The formulations of the present invention allow therapeutic concentrations of SA to be achieved at lower daily doses than for direct-release ASA pharmaceutical formulations, thus reducing the likelihood of their G1-irritating effect.

The pharmaceutical compositions of the present invention can be used in all indications for which the use of ASA is warranted: particularly for rheumatism, arthritis, lumbago, neuralgia, neuritis, mucositis, and fever and cerebral palsy.

Approximately 600-1300 mg, such as 6501300 mg of ASA, is administered every 8-12 hours to produce an anti-inflammatory effect. The daily dose may range from about 2.6 g to about 3.9 g. For pain relief and antipyretics, the recommended dosage range is from about 300 mg to about 700 mg, for example, 325-650 mg. For rheumatic fever, 100 mg / kg body weight / day ASA can be administered in divided doses every 8-12 hours to reduce pain and swelling. For cerebral blood flow attacks, the recommended dose is 650 mg every 12 hours.

The present invention also provides for the preparation of an oral solid pharmaceutical formulation containing at least 300 mg of acetylsalicylic acid in sustained release form and providing a significantly higher concentration of free salicylic acid in plasma in two or three divided doses of 2.6 g / day. , such as those obtained when the immediate release tablets are administered in the same daily dose in divided doses every 4 hours.

The pharmaceutical composition of the present invention preferably contains 300-700 mg of ASA, with a dissolution rate of 15-40% in water at 37 ° C in one hour and at least 70% in 8 hours. Preferably, the composition emits 20-35% within 1 hour; Within 8 hours, the release is preferably 70-90%, for example 80-90%.

The following non-limiting Examples illustrate the process of the invention in more detail in the following Examples:

Microcrystalline cellulose has a molecular weight of 30,000-50,000; an average particle size of 30 to 100 microns; density 1.55; molding volume 0.30-0.80. Avicel PH 102 (Trade Mark, FMC Corporation) was used in the formulations. This product meets the requirements of US XXI. The requirements of the pharmacopoeia for microcrystalline cellulose.

Hydroxypropyl methylcellulose 2208 has an average molecular weight of 120,000 and a viscosity of about 15 Pa.s; it has a methoxy content of 19-24% by weight and a hydroxypropyl content of 4-12% by weight. Methocel K15M Premium was used in the formulations

HU 201875 Β (Trademarked Trade Product, Dow Chemical Company). This product satisfies the United States XXI. Requirements for Hydroxypropyl Methyl Cellulose 2208 in the Pharmacopoeia.

Pregelatinized starch is a modified corn starch containing 5% amylose, 15% amylopectin and 80% unmodified corn starch; partially soluble in cold water. Strach 1500 (Trade Mark, Colorcon Inc., West Point, Pennsylvania, USA) was used. This product burns out the United States XXI. Requirements for pre-gelatinized starch in your pharmacopoeia.

As colloidal silica, Cab-O-Sil (a trade mark product, Cabot Corporation, Boston, Mass., USA), conforming to U.S. Pat. Requirements in the Pharmacopoeia.

The active ingredient was 4mm crystalline ASA. For bioavailability, Bayer's Aspirin (Trademarked Trade Product) was used as the reference as a direct release formulation.

Further details on the above products can be found in the manufacturer's brochures and in the following section; Lexicon Dairy Hilfsstoffe (P.. P. Fiedler), 2nd Edition, 1981, Cantor / Aulendorf Edition, Federal Republic of Germany.

All other ingredients used in the formulations meet the requirements of United States XXI. Requirements in the pharmacopoeia.

Example 1

Preparation of tablets containing 325 mg ASA mg / tablet

ASA 325,000 Microcrystalline cellulose 47,500 (Hydroxypropyl) methylcellulose 27.625 Pregelatinised starch 22.100 stearic 2,125 Colloidal silica 0650

million batches are prepared as follows:

The quantities given above are multiplied by 1 million to use 325 kg of acetylsalicylic acid.

kg of acetylsalicylic acid is mixed with silica. The remaining mixture of acetylsalicylic acid, hydroxypropylmethyl cellulose, silica, microcrystalline cellulose and pregelatinized starch was alternately transferred to a 14 m ³ double-walled mixer, stirred for 15 minutes, and then weighed 40 kg. The remaining mixture was passed through a 20 mesh stainless steel screen (1.00 mm mesh diameter and 0.63 mm filament diameter) through an oscillating granulator. The remaining 40 kg of the non-sieved mixture was blended with stearic acid for 5 minutes, then sieved through the aforementioned 20 mesh stainless steel sieve oscillating granulator and blended with the former sieved mixture. The resulting mixture is vortexed for 15 minutes and the resulting granulate is tabletted on a rotary tablet slot. Each tablet weighs 425 mg, has a thickness of 4.68-4.85 mm and a hardness of 8-12 kiloponds (according to the Heberlein method).

Release data for dissolution (average of 6 tablets) in water at 37 ° C:

Liberation ASA percent Lot 1 Lot 2 In the 1st hour 23.1 30.3 In the 2nd hour 39.4 45.4 At 3 o'clock 51.2 57.0 At 4 o'clock 61.4 65.9 At 6 o'clock 72.5 76.5 At 8 o'clock 80.7 86.6 At 12 o'clock 87.1 93.6

Example 2

Preparation of tablets containing 650 mg ASA Similarly to the procedure described in Example 1, tablets were prepared, each containing the following components:

mg / tablet

ASA 650,000 Microcrystalline cellulose 95,000 (Hydroxypropyl) methylcellulose 55.25 Pregelatinised starch 44.20 stearic 4.25 Colloidal silica 1:30

This batch is sufficient to produce 500,000 tablets. The tablets thus obtained weigh 850 mg each and have a thickness of 6.25-6.40 mm.

Dissolution Release Data (mean of tablet 6) in water at 37 ° C:

The liberated one Lot 1 ASA percent Lot 2 In the 1st hour 21.5 26.8 In the 2nd hour 34.4 39.9 At 3 o'clock 44.2 49.8 At 4 o'clock 53.4 57.7 At 6 o'clock 66.1 69.0 At 8 o'clock 75.7 77.1 At 12 o'clock 86.9 85.7

"The examination

The bioavailability of ASA administered with the composition of the invention at a dose of 1300 mg three times daily is in equilibrium.

The tablet formulation of the invention described in Example 2 (containing 650 mg ASA) was administered to 2 healthy male volunteers at 2 o'clock in the morning at 7 o'clock, then at 15 o'clock and 23 o'clock in the period of 1-8. days, and 7am on the 9th. A total of 3.9 g of ASA was administered daily.

A direct release formulation was administered in the form of tablets containing 325 mg of active ingredient every 4 hours, from 7 am to 2 pm

HU 201875 Β hours from 1-8. days, as well as 7 am and 11 am on day 9. The total daily dose was 3.25 g ASA.

The two formulations were administered over a 9-day study period in a randomized order for each subject. At the end of the study period, a washout period of 6 days was maintained.

Blood samples were taken at 7am (before dosing) and 11am (before dosing) on day 8, and at 7am (before dosing) on day 9, and 1, 2, 3, 4 hours before (dosing) for immediate release formulations), and 5, 6, 8, 10, and 12 hours after administration of the active ingredient at 7 hours.

For both formulations, a statistical evaluation of days 8 and 9 showed that there was an equilibrium condition for the bioavailability study at day 9.

The results obtained in the measurement of free plasma salicylate in the blood are as follows (the reference is a direct release formulation):

Results:

Sampling Day 9 (steady state) is the mean plasma salicylate (hour) concentration in mg / ml

3.9 g / day Example 2 3.25 g / day as reference

2x650 mg Every 8 hours compound 2x325 mg Every 4 hours 0 113.90 + 56.14 * 56.29 36.90 + 1.00 117.91 + 65.02 * 68.55 37.07 + 2.00 114.17 + 57.27 * 72.53 31.12 + 3.00 118.58 + 61.07 * 68.54 39.81 + 4.00 117.15 + 59.25 * 54.49 32.29 + 5.00 115.66 + 58.85 * 67.02 27.50 + 6.00 111.82 + 57.34 * 64.28 21.55 + 8.00 94.20 + 57.19 * 54.57 29.53 + 10.00 82.82 + 49.36 * 41.94 26.46 + 12.00 68.11 + 52.07 * 30.02 23.23 +

* At 5% or higher, the two formulations are statistically different

Salicylate pharmacokinetic parameters at steady state on day 9

Example 2 references as compound compound 2x650 mg 2x325 mg Every 8 hours Every 4 hours

0-8 hour AUC

(Pg-hr / ml) 902.35 + 456.88 * 510.26 227.46 + Cmax (mg / ml) 128.00+ 60.54 * 83.81+ 33.20 Tmax (hour) 3.08+ 1.51 3.42+ 1.88 tl / 2 (hour) 10.15+ 5.38 * 5.00+ 2.37 * K _e i (hours ⁴ ) ¹ ) 0.09+ 0.04 * 0.17+ 0.09 *

* Statistically different at levels of 5% or higher; calculation with the data observed after the second dosing.

1) Emptying constant

Relative 0-8 hour AUC (%) 177.26 + 57.61 Relative Cmax (%) 153.18 + 47.92

Evaluation of results

Statistical evaluation of steady state plasma salicylate concentrations by appropriate statistical tests (double t-tests) showed that the formulation of Example 2 resulted in significantly higher plasma concentrations at all times. The increase in plasma free salicylate concentration is greater than expected, even when the reference formulation is administered at a dose of 3.9 g. Statistical evaluation showed that the mean AUC and Cmax of--8 hours were significantly higher for the formulation of Example 2. Adjusting the 0-8 hour mean AUC to a dose of 3.9 g for each product would result in a 147% bioavailability of the formulation of Example 2 of the present invention compared to the reference formulation. The composition of Example 2 gives a significantly longer half-life and a lower Kel.

On day 9, the concentration of total salicylate in the urine collected for 24 hours was determined. THE

1488.42 + 531.08 mg for Example 2; for the reference preparation, this value was 1265.97 ± 572.16 mg; these values are similar.

Test "S"

The bioavailability of ASA administered with the composition of the invention twice daily is 1300 mg at steady state.

The tablet formulation of the invention described in Example 2 (containing 650 mg ASA) was administered to 2 healthy male volunteers in 2 tablet doses. Three of the subjects participated in the previous A test at 7 am and 7 pm for 8 days, with the last dose being given at 7 am on day 9. A total of 2.6 g of ASA was administered daily. The experiment was conducted as above except for the lower dose.

Statistical evaluation on days 8 and 9 showed that on day 9 equilibrium was reached.

The following table summarizes the results obtained 12 hours after drug administration.

On day 9 (steady state), the mean plasma salicylate concentration in pg / ml of the compound of Example 2

The sampling time is 2x650 mg (hour) every 12 hours

49.70 21.16 +

1.0 54.82 ^ 22.75

2.0 85.72 + 22.53

3.0 62.19 + 23.31

4.0 59.90 + 23.18

5.0 55.87 + 25.84

6.0 55.18 + 22.04

8.0 47.22 + 24.77

10.0 42.98 + 24.19

12.0 34.72 + 20.09

HU 201875 Β

The 0-8 hour AUC is calculated

446 ± 182.46 mg-h / ml.

Cmax was 64.11 ± 21.78 pg / ml.

The results show that when 1300 mg of ASA is administered twice a day, a total of 2.6 g of ASA from the composition of the invention, it produces a concentration of free salicylate in plasma as when administered five times daily. 650 mg of ASA, i.e. a total of 3.25 g of ASA, is added in a direct release formulation.

Again, total SA concentrations in urine collected for 24 hours were measured. The cumulative total amount of SA was 1322 ± 162 mg; this value is similar to that obtained in Test A.

Claims (26)

PATIENT INDIVIDUAL POINTS A process for the preparation of a sustained release pharmaceutical composition comprising acetylsalicylic acid with a) microcrystalline cellulose and b) hydroxypropylmethylcellulose such that component a) relative to component b) is 10: It is used in a weight ratio of 1 to 1: 1 and the resulting mixture is mixed with conventional excipients to form a pharmaceutical composition. 2. The method of claim 1, wherein the tablet form is a unit dosage form. 3. The method according to claim 1 or 2, wherein 300 to 700 mg of acetylsalicylic acid is used as a pharmacologically active component in the tablet-like dosage unit. 4. The method of claim 3, wherein 325 mg of acetylsalicylic acid are used as the pharmacologically active component. 5. The method of claim 3, wherein the pharmacologically active component is 650 mg acetylsalicylic acid. 6. Process according to any one of claims 1 to 3, characterized in that microcrystalline cellulose having an average degree of polymerization from 200 to 2000 is used. 7. Process according to any one of claims 1 to 3, characterized in that microcrystalline cellulose having an average molecular weight of from 20 to 100,000 is used. 8. Process according to any one of claims 1 to 4, characterized in that microcrystalline cellulose having an average molecular weight of from 30 to 50,000 is used. 9. Process according to any one of claims 1 to 4, characterized in that microcrystalline cellulose having a density of 1.40 to 1.60 is used. 10. References 1-9. A method according to any one of claims 1 to 3, wherein the microcrystalline cellulose is a commercial product labeled AvicelR. 11. Referring to Figs. Process according to any one of claims 1 to 4, characterized in that the composition comprises (hydroxypropyl) methylcellulose having a methoxy content of from 15 to 34% by weight. 12. Process according to any one of claims 1 to 3, characterized in that a hydroxypropylmethylcellulose having a methoxy content of from 19% to 24% by weight is used. 13. Referring to FIGS. A process according to any one of claims 1 to 3, wherein the hydroxypropylmethylcellulose has a hydroxyl content of from 4% to 32% by weight. 14. References 1-13. Process according to any one of claims 1 to 3, characterized in that a hydroxypropylmethylcellulose having a hydroxyl content of from 4% to 12% by weight is used. 15. Referring to Figures 1-14. A process according to any one of claims 1 to 3, characterized in that it uses (hydroxypropyl) methylcellulose having a viscosity in an aqueous solution of 2% by weight at 20 ° C from 0.015 Pa.s to 50 Pa.s. 16. The method of claim 15, wherein said hydroxypropylmethylcellulose has a viscosity of from 4 Pa.s to 50 Pa.s. 17. References 1-16. Process according to any one of claims 1 to 3, characterized in that (hydroxypropyl) methylcellulose having an average molecular weight of from 20 to 200,000 is used. 18. References 1-17. Process according to any one of claims 1 to 3, characterized in that (hydroxypropyl) methylcellulose having an average molecular weight of from 90 to 130,000 is used. 19. References 1-18. Process according to any one of claims 1 to 3, characterized in that Methocel ^{R is} a commercially-labeled commercial product (hydroxypropyl) methylcellulose. 20. Referring to Figures 1-19. Process according to any one of claims 1 to 4, characterized in that the microcrystalline cellulose is used in a weight ratio of from 10: 1 to 1: 1 relative to hydroxypropylmethylcellulose. 21. The method of 1-20. Process according to any one of claims 1 to 4, characterized in that the microcrystalline cellulose is used in a weight ratio of from 3: 1 to 1: 1 relative to hydroxypropyl methylcellulose. 22. Referring to FIGS. Process according to any one of claims 1 to 5, characterized in that the microcrystalline cellulose is used in a weight ratio of from 1: 5 to 1:10 relative to the pharmacologically active component. 23. The method of 1-22. A method according to any one of claims 1 to 4, wherein the microcrystalline cellulose is used in a weight ratio of 1: 6 to 1: 7.5 relative to the pharmacologically active component. 24. References 1-23. Process according to any one of claims 1 to 3, characterized in that the composition comprises pre-gelatinized starch. 25. The method of 1-24. Process according to any one of claims 1 to 4, characterized in that the pregelatinized starch is used in a weight ratio of 1: 1 to 1: 5 relative to (hydroxypropyl) methylcellulose. 26. A process according to any one of claims 1 to 3, characterized in that the pharmacologically active component is used in a weight ratio of from 2: 1 to 4: 1 relative to the total weight of all the other components.