JP2003192582A - Rapid release tablet containing naproxen sodium - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To produce new tablets of naproxen sodium having rapidly dissolving property. <P>SOLUTION: The naproxen sodium tablets comprise naproxen sodium and a spray-dried mannitol. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention is directed to a method of making a new tablet having improved dissolution rate of naproxen sodium and its formulation.

[0002]

Naproxen sodium is a known anti-inflammatory, analgesic, antipyretic agent for use in acute and chronic rheumatoid arthritis, osteoarthritis, primary dysmenorrhea and for the relief of mild to moderate pain. This is about 2
It has been approved in many countries around the world for zero years and has a profile that favors extremely safe risk factors. In the United States, for example, ALEVE® (Bay
er company Consumer Care Division Morristown NJ), and the generic name Naproxan sodium tablet (Rite-Aid Corporation, Harrisburg PA
Are commercially available). The chemical name of sodium naproxen is (-)-6-methoxy-alpha-methyl-2-naphthalene acetic acid sodium salt.

A rapid onset of action is required, especially when using naproxen tablets for the treatment of pain,
And it's highly desirable. WO 98/35666 A1 describes tablets containing naproxen nanoparticles on the surface of which surface modifiers and other excipients have been adsorbed. Naproxen nanoparticles are obtained by wet milling naproxen with a surface modifier, separating the resulting surface modified particles, spray drying and sieving. Therefore, the manufacture of solid formulations is complicated and expensive.

WO belonging to the same company as WO 98/35666 A1
00/13672 A1 describes a solid nanoparticulate formulation obtained by compression of naproxen nanoparticles with a surface modifier and an alkalizing agent co-adsorbed on the surface. WO 00
Since / 13672 A1 contains no details regarding the production of nanoparticles, it is clear that they were produced in the same way as described in WO 98/35666 A1. Therefore, WO
The same situation described for 98/35666 A1 is WO 00/13672
Applies to A1.

EP 0 636 363 B1 discloses a rapidly disintegrating tablet which dissolves in the mouth and contains at least the active ingredient coated with a taste-masking coating, a carbohydrate and a binder. Generally such formulations are sensitive to breakage and require extremely careful handling, including manufacturing, packaging, shipping and control. Furthermore, naproxen is mentioned as the active ingredient, but does not show its embodiment.

[0006]

The object of the present invention is for naproxen sodium, which has a rapid dissolution rate in vitro as well as a rapid absorption rate, a reduced variability of fasted / fed animals in vivo, and is simple and It is to provide a new formulation that can be manufactured at low cost.

[0007]

It has been discovered that solid naproxen sodium formulations with rapid solubility are obtained when compressing a mixture containing sodium naproxen and spray-dried mannitol into tablets. Therefore,
The present invention is directed to tablets for immediate release of naproxen sodium containing naproxen sodium and spray dried mannitol.

The spray dried mannitol used as an ingredient for tablet making is preferably a mass median particle diam of 75-300 microns.
eter), fluidity of 25-45 degrees, 0.35-0.75g
/ Ml loose density and 0.45
It has a tapped density of ˜0.85 g / ml. More preferably the spray dried mannitol used as an ingredient for the manufacture of tablets is 75-300.
Massive median particle size of micron, fluidity of 25-40 degrees,
Loose density of 0.40-0.60 g / ml and
Tap packing density of 0.50 to 0.75 g / ml (tapped
density).

The spray-dried mannitol used for tablet manufacture is most preferably a large median particle size of 75-250 microns, a flowability of about 31 degrees, about 0.51 g / g.
It has a loose density of ml and a tapped density of about 0.60 g / ml. Spray-dried mannitol having the above physical properties was prepared from Merck KGaA to Par.
It is sold under the trade name teck M200.

As used herein, "fluidity" is the angle of response measured from a ridge that is carefully made by dropping the material through a vibrating screen and glass funnel on a horizontal plane using a mechanical lever. It is described by. It is understood that all values used in this application for "fluidity" have been measured by the method defined in ISO 4324.

As used herein, "loose density" is defined as the apparent density of a powder, calculated as the mass (weight) to volume ratio, which mass is placed in a calibrated cylinder. Defined by a specific amount of powder, the volume of which is defined as the volume of this particular calibrated cylinder.
It is to be understood that all values given in this application for "loose density" have been measured by the method defined in DIN, EN, ISO60.

As used herein, "compressed density" is the ratio of mass (weight) to volume obtained in the same manner as described for "loose density", except that 1250 cylinders The only difference is that after hitting, the volume used for the calculation of "compressed density" is determined. All values in this application for "compressed density" are DIN, EN, ISO
It should be understood that it was measured by the method defined in 787-11. Spray-dried mannitol is present in the tablets of the invention in an amount of 10-90% by weight, preferably 30-70% by weight.

As used herein, "spray-dried mannitol" is obtained by spray-drying a solution and / or suspension of mannitol. Spray drying method and /
Alternatively, in order to improve the physicochemical properties of spray-dried mannitol, the solution / suspension used for its preparation contains 0.1 to 20% by weight of other polyols such as sorbitol or lactitol (total amount of polyols). Can be included). Thus, the spray dried mannitol used to make the tablets of the present invention may contain up to 20% by weight of other polyols. Preferably the spray dried mannitol used contains 0.5 to 2.0% by weight of polyol, more preferably about 1% by weight. The polyol which can be additionally present in the spray-dried mannitol is preferably sorbitol. A method that can be used for the production of spray dried mannitol for use in this case is described in WO 97/39739 A2.

Advantageously, the tablets according to the invention further comprise lubricants and / or lubricants. Lubricants and / or lubricants are intended to improve the processing of the mixture of naproxen sodium used for tablet making, and thus achieve better tablet quality. Lubricants / lubricants which can be used are, for example, fumigated or colloidal silica, stearates (eg magnesium stearate, calcium stearate, stearic acid), talc, polyethylene glycol, starch, sodium stearyl fumarate, Includes magnesium lauryl sulfate and sodium lauryl sulfate. Magnesium stearate or sodium stearyl fumarate are preferred. When using,
The lubricant / lubricant is present in a ratio of 0.1 to 10% by weight.

In addition, other adjuvants such as diluents or disintegrants may be included in the tablets of the invention. Diluents which can be used are, for example, dextrose, dicalcium phosphate, lactose, microcrystalline cellulose, sodium chloride or sucrose. Disintegrators that can be used are, for example, starch, cation exchange resins, polyvinylpyrrolidone, modified starches, microcrystalline materials (for example microcrystalline cellulose), alginic acid, sodium starch glycolate, modified celluloses or gums. Diluent and / or disintegrant may be 10 to 90% by weight and / or 5 to 9%, respectively.
It may be present in the tablets of the invention in an amount of 0% by weight.

The tablets of the present invention can be readily manufactured by mixing the ingredients and compressing the mixture into tablets. Accordingly, the present invention is also directed to a method of making the tablets of the present invention, characterized in that the ingredients present in the tablets are mixed together and compressed into tablets.

Compressing a mixture containing all the ingredients of the tablet of the invention into tablets can be done by using a conventional tablet machine. Although tablet processing parameters such as compression force affect the dissolution rate of tablets,
The dissolution properties of tablets are influenced mainly by the composition of the mixture used for compression. Therefore, the present invention is also directed to mixtures that can be used to make the tablets of the present invention. Its characteristic is that the mixture contains the ingredients present in the tablet.

[0018]

The following examples are given to illustrate the present invention. However, it should be understood that the invention should not be limited to the particular conditions or details described in these examples. Example 1: Formulation A Composition of immediate release tablet Naproxen sodium 220 mg Median particle size 91 micron Parteck M200 (spray dried mannitol) 469.5 mg PRUV® (sodium stearyl fumarate) 10.5 mg Blending method

The ingredients were passed through a # 20 mesh screen to remove lumps. Naproxen Sodium and Parteck M200
Was added to a 2-Qt V-blender and blended for 4 minutes. The rest of Parteck 200M was added and blended for an additional 4 minutes. Sodium stearyl fumarate (previously passed through a # 40 mesh or finer sieve) was added to the blender and blended for an additional 4 minutes. The blended product was taken out and stored until tableting.

Tablet Molding Tablets were manufactured on a Kilian 28A tablet press. The tablet press speed was set to 30 rpm. The punch used is 9
/ 16 inch, and S.I. S. It was a concave type and a bevel edge type. The compression force was adjusted to achieve a tablet hardness of about 8KP. Tablets were collected and stored for inspection.

Example 2: Formulation B Composition Naproxen sodium 220 mg (median particle size 60 microns) Parteck M200 (spray dried mannitol) 671 mg magnesium stearate 9 mg Tablets were mixed using the same method as described in Example 1 Compressed to.

Example 3: Formulation C Composition Naproxen sodium 220 mg Median particle size 91 microns Parteck M200 (spray dried mannitol) 469.5 mg Magnesium stearate 7 mg Cab-O-Sil 3.5 mg The ingredients were mixed and described in Example 1. Compressed into tablets using the same method as.

Comparative Example: Formulation D The same ingredients were mixed as in Formulation B (Example 2) except that granular mannitol was used in place of spray dried mannitol, and tablets were formed using the same method as described in Example 2. Compressed.

Example 4 In Vitro Release of Naproxen Sodium The dissolution test is according to USP-24 apparatus-2 (with stirrer) using 900 ml of phosphate buffer pH 7.4 37.
The stirring speed was 50 rpm. Phosphate buffer pH 7.4 (0.1 mol) was prepared by dissolving 2.62 g of monobasic sodium phosphate and 11.50 g of anhydrous dibasic sodium phosphate in water to 1000 ml. The emission rate was determined photometrically at a wavelength of λ = 332 nm.

Dissolution rates were determined for Formulations A, B and C described in Examples 1 to 3 and for comparison, Formulation D prepared by using granular mannitol.
In addition, a commercial rapid release prescription brand name Bayer Al
The generic name of eve (registered trademark), Rite-Aid, Inc. was also obtained. The dissolution data obtained are shown in Table 1 (mean ± at least 3 samples / standard deviation of readings; nd = not determined) in percent dissolution.

According to the product description, Aleve®
Contains 220 mg sodium naproxen, microcrystalline cellulose (MCC), Povidone, magnesium stearate, talc, and Opadry-YS-1-4215. Ri
te-Aid is 220 mg naproxen sodium, MCC,
Contains Croscarmellose Sodium, Povidone, Talc, Colloidal Silicon Dioxide, Magnesium Stearate, and Opadry-Ys. (This is HPMC, PEG, Polysorbate-80, Titanium Dioxide, F, D
& C Blue # 2A1. Reiki included)

[Table 1]

The results clearly show that the tablets according to the invention have an improved dissolution rate compared to the tablets already on the market. Furthermore, the tablets of the invention containing spray-dried mannitol also have a faster dissolution rate compared to tablets containing granular mannitol (instead of spray-dried mannitol).

Bioavailability study A comparative, randomized, single dose, double crossover bioavailability study of naproxen sodium 220 mg oral tablets was performed on 24 healthy rabbits under fasted and fed conditions. (Trademark) formulation A. The test drug (naproxen sodium 220 mg tablet) was administered in a randomized manner by oral administration in quadrants (55 mg) of the tablet. The washout period for all experimental animals was 7 days. Twelve (1-12) healthy rabbits were used in the fasted state test, while the other 12 (13-24) healthy rabbits were used in the fed state test. Blood samples were taken at time intervals of up to 4 hours after administration and tested for naproxen by high performance liquid chromatography (HPLC).

Pharmacokinetic parameters were determined by standard non-compartmental analysis, followed by Kinetica (Kinetica).
etica) program was used for statistical analysis of variance tests. The pharmacokinetic data obtained are summarized in Table 2.

[Table 2]

The data show that the tablet of naproxen sodium of the present invention has a shorter time (t _max ) to reach the peak of plasma concentration in both the fed and fasted states as compared with Aleve (registered trademark) Concentration (c _max )
Clearly shows that Furthermore, there was less variability in the time to reach the fasted peak plasma concentration compared to the fed state. Therefore, the tablets of the present invention provide a faster onset of action and a stronger effect, which is particularly advantageous if the tablets are used for pain treatment. Furthermore,
Since the bioavailability (AUC) of the tablets of the present invention is increased, the same effect can be obtained with lower doses of naproxen natrim, thus reducing the amount of naproxen sodium present in the tablets.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 19/02 A61P 19/02 29/00 29/00 101 101 (71) Applicant 591032596 Frankfurter Str. 250, D-64293 Darmstadt, Federal Repeat of Germany (72) Inventor Armat Al-Gazawe, England 8 7A, UK, Waltham Cross, Crossroads, Maple Leaf Court 33 (72) Inventor Karyan S. Nuggle United States 08051 Heater Drive South, Mantua, NY 22 (72) Inventor Dan Ef. Jean Baptist United States 10509 Indian Hill Road 35F Term, Brewster, NY (Reference) 4C076 AA37 BB01 CC05 DD38B DD41C DD47C FF33 GG14 4C206 AA01 AA02 DB13 KA04 MA03 MA05 MA55 MA72 NA20 ZA07 ZA08 ZA96 ZB11 ZB15

Claims (10)

[Claims] 1. An immediate release tablet of naproxen sodium containing naproxen sodium and spray dried mannitol. 2. The spray-dried mannitol used for tableting has a mass median particle size of 75 to 300 microns, a flowability of 25 to 45 degrees, a loose density of 0.35 to 0.75 g / ml and a 0.45 to 0.85. The tablet according to claim 1, characterized in that it has a tap density of g / ml. 3. The spray-dried mannitol used for tableting has a mass median particle size of 75 to 300 microns, a flowability of 25 to 45 degrees, a loose density of 0.40 to 0.60 g / ml and a 0.50 to 0.75. A tablet according to claim 1 or 2, characterized in that it has a tap density of g / ml. 4. The spray-dried mannitol used for tableting has a mass median particle size of 75 to 250 microns, a flowability of about 31 degrees, a loose density of about 0.51 g / ml, and about 0.60 g / ml. The tablet according to any one of claims 1 to 3, having a tap density of. 5. The tablet according to any one of claims 1 to 4, characterized in that the tablet further comprises a lubricant and / or a lubricant. 6. Tablet according to claim 5, characterized in that the lubricant is magnesium stearate and / or sodium stearyl fumarate. 7. A spray-dried mannitol of 10-90.
A tablet according to any of claims 1 to 6, characterized in that it is present in the tablet in an amount of% by weight. 8. The spray dried mannitol is 30-70.
The tablet according to claim 7, characterized in that it is present in the tablet in an amount of% by weight. 9. A mixture which can be used for the production of an immediate release tablet of sodium naproxen, characterized in that the mixture comprises the components according to any of claims 1-8. 10. The method for producing a tablet according to claim 1, wherein the ingredients present in the tablet are mixed and compressed to give a tablet.