JPS6072813A - Release-controlled naproxen and sodium naproxen tablet - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to t-H-6-methoxy-alphamethyl-2-naphthaleneacetic acid (naproxen) and its pharmaceutically acceptable sodium salt (naproxen). sodium)
The present invention relates to a controlled release formulation of the invention. In particular, the invention relates to an oral dosage form of naproxen or naproxen sodium homogeneously dispersed in a matrix of hydroxypropyl methylcellulose, providing a release period suitable for daily administration and good bioavailability. be.

(Related prior art) Naproxen and naproxen sodium are known for their analgesic,
It is well known and widely used as an anti-inflammatory agent with antipyretic effects. These generally reduce pain and inflammation,
and used to relieve certain conditions such as arthritis and dysmenorrhea. Naproxen is 250 q/, 375
It is commercially available as ~, and 500~ tablets, generally 50~ per day.
Therapeutic doses of 0-1000 mg are administered at 8-12 hour intervals.

Naproxen sodium is commercially available as 275 tablets and is generally given in therapeutic doses of 8-12 tablets per day.
Administered at intervals of hours.

Hydroxypropyl methylcellulose is Methocel E,
Various trademarks including F, J and K (all formerly known as Methocel HG, Dow Chemical Co., USA), HPM (British Celanese Co., UK), and Metroose SH (Shin-Etsu Co., Ltd., Japan). quality products are commercially available. The various qualities of products available under the above trademarks differ in methoxy and hydroxypropoxy content, as well as in molecular weight and viscosity. Commercial kettles of various hydroxypropyl methylcelluloses reflect their respective viscosity types and are tested for 2% aqueous solutions at 20°C'? Based on the measured viscosity. The viscosity range is about 15ooo to 15ooo.

The number average molecular weight of -L is shown below. Various grades of the above trade names are, for example, 50 cps, 100 cps, 4
It is a single viscosity type hydroxypropyl methylcellulose such as 000CPli, 15000 cps.

The field of controlled release drugs is gaining importance in the formulation, manufacturing and marketing of new drugs. Technologies and corresponding products in this field are particularly relevant to extended release, controlled release, sustained release, depot, etc.
It is described as a preservative, delayed-acting, delayed-release, single-dose release drug, etc. In this invention, the term "controlled release" indicates that control is observed over both the duration and characteristics of the in vivo drug release curve.

Controlled release pharmaceutical dosage forms have a number of advantages over conventional dosage forms for individual pharmaceuticals. Of major experimental and therapeutic importance is the reduction in the number of doses required to obtain the desired effect. The once-daily dosage form significantly reduces the burden on the patient and extends the effect of the drug into the night, thereby ensuring that the patient's sleep is not disturbed until the morning. Increasing the acceptability of drug therapy improves patient burden and therefore treatment.

Another important therapeutic advantage of certain controlled release pharmaceutical dosage forms is reduced fluctuations in plasma drug concentrations. The pharmacological basis for suppressing fluctuations in plasma drug concentrations is based on three basic principles. First, all drugs have therapeutic blood levels that must be reached when their use is to have an initial effect. When a therapeutic condition requires multiple administrations over an extended period of time, the therapeutic blood level is the pharmaceutical level that should maintain maximal drug efficacy. Second, most drugs have toxic blood concentrations that represent a threshold at which adverse effects or side effects occur. Third, the drug concentration response curves for most drugs are such that activity is proportional to the logarithm of concentration. From these pharmacological principles, a logical basis for tightly maintaining plasma drug levels is deduced. Several years of clinical experiments have supported the above rationale and now show that when continuous drug administration is desired, optimal treatment is obtained when plasma drug concentrations are maintained near therapeutic levels. is widely accepted.

Techniques for drug administration affect the time course of therapeutic activity by influencing the characteristics of blood drug concentrations. Conventional pharmaceutical dosage forms are rapidly absorbed and metabolized into the circulatory system. Typical blood level characteristics after a single dose in the conventional manner are an initial high peak, then a rapid decline,
Its slope and duration will vary depending on factors such as the drug's half-life. The first high peak significantly exceeds the normal therapeutic plasma concentration range and represents the majority of the drug contained in the dosage form. After multiple regular doses, a steady-state mean plasma drug concentration is achieved, but absolute levels fluctuate up and down with peaks and troughs.

In contrast, controlled drug dosage forms can prolong the duration of therapeutic drug levels in the blood and reduce or avoid the initial spike in blood concentration levels that is characteristic of traditional dosage forms. can do. Furthermore, although controlled-release oral dosage forms do not inherently reduce fluctuations in blood drug concentrations, there is an opportunity to minimize these fluctuations based on the fact that the rate of drug release is measured over long periods of time (11). is obtained.

Reduction of plasma drug level fluctuations is achieved by balancing the drug's pharmacodynamics, i.e., absorption, distribution, metabolism, and excretion rate with in vivo release rate such that changes in plasma drug levels are minimized. The time course of changes in blood drug concentration is the ultimate result of the rate of release into the body and the pharmacodynamic behavior of the drug.

Conventional dosage forms for naproxen and naproxen sodium have been administered twice or twice a day to maintain therapeutic levels and to minimize the difference between peak and trough blood levels during multidose therapy. Administered 3 times. Such methods typically have a peak-to-trough ratio of approximately 2.
: Becomes 1. In order to maximize the therapeutic efficacy of a drug, it is desirable to minimize the peak-to-trough ratio obtained with multiple dose therapy. Controlled release formulations allow generally accepted blood level peak-to-trough ratios to be obtained with less frequent dosing.

Numerous types of controlled release oral dosage forms have been developed (12), all of which have drawbacks that affect their suitability for the individual drug and therapeutic subject. For the design of controlled drug release formulations, extensive variations in the physicochemical and pharmacodynamic properties of various drugs mean that formulations suitable for one drug will generally not be applicable to other drugs. It imposes various demands that cannot be predicted. Formulations that combine a drug with a soluble or edible IJx are easy to manufacture;
It is desirable because it has little variation between lofts and is relatively inexpensive. The use of hydrophilic gums such as hydroxypropyl methylcellulose in sustained release matrix materials is known and has been used with a variety of active ingredients. However, no formulation of this type suitable for controlled release of naproxen and naproxen sodium is known.

Christenson and Doll (U.S. Pat. No. 306,514)
No. 3) discloses the use of certain hydrophilic gums containing hydroxypropyl methylcellulose as carrier bases for the manufacture of sustained release pharmaceutical tablets. This tablet is
It essentially consists of a mixture of a drug and at least one third part by weight of a hydrophilic gum. Examples 1 and 7 are [
) describes the use of Methocel 60HG4000 cps (now called Methocel E4M), which has a number average molecular weight of 93,000, calculated from data in ``Methocel Cellulose Ether Products'' (The Dow Chemical Company, 1974). ing. Example 4 is Methocel 9
Q) Ic400'OCps, Example 5 is Methocel 90H
G15000 cps (currently Methocel E4M
and 15M). Grades with viscosities of 4,000 cpH and 15 o o o cps have polymers with number average molecular weights of 89,000 and 12
4000 respectively. The ratio of polymer to drug in the examples ranges from 1:2 to 10=1;
It is stated that the duration and release time are up to 12 hours in vitro.

Shore and Nigaraie (US Pat. No. 4,369,172, 1983) describe the use of certain hydroxybubutyl methylcelluloses for "extended release therapeutic compositions." In this case, the carrier base has a number average molecular weight of 50
000 and a hydroxypropyl content of 9-12%. Examples cited that correspond to this standard are Methocel E5
Example 1
-4 describes a tablet that essentially mixes about 57% by weight of one or the other of these two materials with lithium carbonate. The tablets weigh approximately 700 kg and release the active ingredient in vitro over a period of 14 hours. Examples 5-6 describe extended release aspirin tablets in which the hydroxypropyl methylcellulose carrier base constitutes 16.5% of the total tablet weight. Another example in US Pat. No. 4,369,172 shows tablets containing 16-20% by weight of polymer and releasing the active ingredient in vitro over a period of 1-6 hours.

The Dow Chemical Company published a pamphlet titled ``Formulation of Extended Release Pharmaceutical Products Using Methocel (15)'' (1982), which described various commercially available Methocel polymers, their relative viscosities, and hydration. The identification of velocity and gel strength properties is described.

This brochure also proposes formulation standards for sustained release pharmaceutical products.

The concept of using hydroxypropyl methylcellulose in oral dosage forms to prolong the rate of drug release into the blood is known, and sustained release of various active ingredients from such dosage forms has not been proposed. However, the technology for formulating oral controlled release forms of naproxen and naproxen sodium has had several drawbacks.

First, as is apparent from the discussion of the related art above, sustained release tablets known in the art rely on fairly high levels of hydroxypropyl methylcellulose to continue the release of drug for a reasonable period of time. The main problem with using such formulations is that they require coarse bulk to obtain tablets. For dry oral dosage forms, there is an approximate upper limit on the tablet bulk that can be tolerated by the patient. This upper limit varies from patient to patient, but can be as low as 650 and up.

Therefore, for a drug such as naproxen, where the therapeutic dose range is 500-1200q7 days, the additional tablet bulk created by including a substantial amount of matrix material is
making the tablets difficult to tolerate for many patients.

Furthermore, although the prior art has demonstrated sustained drug release in vitro from several formulations using hydroxypropyl methylcellulose, the pharmacodynamics, absorption, distribution, metabolism and excretion of drug release in vivo have been shown to improve the ability of controlled release. This imposes more demands on the formulation of sex tablets than can be learned from in vitro experiments. This invention provides sustained plasma therapeutic drug levels for at least 24 hours and provides 4-9
The present invention relates to a novel controlled-release oral dosage formulation of napra mitten or napsisen sodium which requires surprisingly small amounts of hydroxypropylkimethylcellulose by weight. In this invention, the low level of matrix material required makes the naproxen compound of a weight and size that makes it practically suitable and tolerable for administration to patients, and does not require excessive bulk. Alternatively, it becomes possible to manufacture a once-daily dosage form of naproxen sodium. Additionally, long-term once-daily administration of the controlled-release tablets of this invention results in plasma drug concentrations that are less variable than those obtained with long-term twice-daily administration of conventional naproxen and naproxen sodium tablets.

Furthermore, this new formulation is advantageous from a manufacturing standpoint as it requires only three ingredients: naproxen or naproxen sodium, hydroxypropylmethylcellulose and a lubricant.

[Summary of the invention]

The present invention provides a controlled-release tablet for once-daily sunset administration of 500-1200q of naproxen or naproxen sodium, wherein the tablet has a dosage of about 80,000 to about 13
about 4-9% by weight of hydroxypropyl methyl cellulose with a number average molecule t in the range of 0,000, about 81-96% by weight of naproxen or naproxen sodium, 0.1 to about 2% by weight of a pharmaceutically acceptable lubricant, and others. Controlled release tablets made of a matrix comprised of 0 to about 8% by weight of pharmaceutically acceptable excipients.

101 [Description of the Drawings] Figure 1 shows two 750 nl cape discharges produced by the method of the present invention described in Examples 13 and 2 (machines A and B) with the test results described in Example 3. Figure 2 is a diagram comparing plasma naproxen levels over 48 hours achieved by a single dose of the formulation and a single dose of naproxen under the trade name Naprosyn (line C).

FIG. 2 is a graph showing the mean naproxen concentration in plasma over a 24-hour period on day 5 of the multiple dose experiment, with υ- in the test results described in Example 5. The average naproxen concentration in plasma was 750 to 750 F'lf when administered once daily with a controlled-release injection formulation according to the invention (Formulation B in Example 2, line B in Figure 2), or with naproxen 375 F'lf (trade name Naprosyn).
Steady-state levels achieved by dosing RC) every 12 hours in Figure i-2.

FIG. 3 and FIG. 4 respectively show the first example in Example 6.
Plasma naproxen concentrations are shown on days 2, 177, B is once-daily administration of controlled-release tablets, and C is commercially available (
Figure 3 shows the curve obtained with twice-daily administration of Naprosyn (trade name).

[Detailed description of the invention]

Accordingly, this invention provides a controlled release tablet for once-daily oral administration of naproxen or naproxen sodium from 500 to 1200 mg, wherein said tablet has a dosage of about 500 to 1200 mg.
Hydroxypropyl methylcellulose WE having a number average molecular weight ranging from about 130,000 to 4-9% by weight, about 8% naproxen or naproxen sodium
1-96% by weight, 0.1 to about 2% by weight of a pharmaceutically acceptable lubricant, and 0 other pharmaceutically acceptable excipients.
The present invention provides a controlled release tablet made of a homogeneous matrix of from about 8% by weight to about 8% by weight.

The tablet matrix contains small amounts of pharmaceutically acceptable lubricants, such as magnesium stearate, to aid in the tabletting process. This amount generally varies between about 0.1 and 2%, preferably using about 1% of the total weight of the tablet. Suitable tablet lubricants include magnesium stearate, stearic (20) acid, calcium nutearate, and mixtures thereof. Among them, magnesium stearate is preferred.

If desired, the tablet matrix can include other pharmaceutically acceptable excipients such as colorant 2 and glident. Suitable colorants include, but are not limited to, FD&C Yellow No. 5, FD&C Yellow 6%, v, and FD&C Blue No. 2, which are commonly Use an amount equal to or less than 1% of the tablet weight. Suitable glidents include, but are not limited to, pharmaceutical grade talc 2 and m-oriented silica, which are typically used at 7% or less of the tablet weight.

In this invention, the term matrix refers to a homogeneous mixture of naproxen, hydroxypropyl methylcellulose, lubricant and other optional excipients. One of the essential features of this invention is that the hydroxymethylcellulone is uniformly dispersed throughout the matrix;
Uniform drug release is achieved. The matrix can be prepared by any pharmaceutically acceptable technique for uniform mixing, including dry mixing, conventional wet granulation, compression granulation, 2 and fluidized bed granulation. Tablets can be manufactured from the resulting matrix by known tabletting techniques.

According to this invention, the base Ui of naproxen or naproxen sodium contained in the tablet is 500η and about 1200η.
” / in the range between 1 tablet and about 500-1100
Therapeutic amounts of ~ are indicated for the treatment of pain in arthritis, dysmenorrhea and other conditions.

The tablets of this invention can be administered once a day, i.e. once within 24 hours.
Provides a release period suitable for multiple administrations. Generally, naproxen and naproxen sodium are administered at doses of 500-550 to 70 mg per day, depending on the physician's judgment based on the patient's needs.
It is administered at a level of 50-800yli or 1000-1100/ny. Naproxen is usually 500,7 per day
Naproxen sodium is usually administered at levels of 550 or 1100"P per day.

The hydroxypropyl methylcellulose used in this invention is a water-bathable cellulose ether filter and is commercially available in various qualities under the trade names mentioned in the Background of the Invention section. The physicochemical properties of these polymers vary widely. A suitable bar for use in this invention is FJ80000-1300.
It is a mono-viscosity, premium grade polymer with a number average molecular weight in the range of 0.

The number average molecular weight of the hydroxypropyl methylcellulose used in the tablet matrix significantly influences the resulting release characteristics. The number average molecular weight (Mn) is calculated by dividing the molecular weight of each molecule in a representative sample population by the number of molecules in the sample, and is the limit of the solvent when the concentration of hydroxypropyl methyl cellulose approaches zero. Calculated from osmotic pressure. Hydroxyzorohirmethylshironuha, If18
0,000 to about 130,000, preferably about 120,000 (23
) to about 130,000. When the polymer has a number average molecular weight of 120,000-130,000, it is desirable to constitute about 4-6 weight percent of the naproxen controlled release tablet or about 6-8 weight percent of the naproxen sodium controlled release tablet. A second preferred number average molecular weight range is about 85,000 to about 95,000.

When the polymer has a number average molecular weight in this range, it desirably constitutes about 7-9 weight percent of the Naproxen Sodium Controlled Release Tablet.

Hydroxypropyl methylcellulose having a range of number average molecular weights suitable for use in tablet matrices is available as a mono-viscosity polymer. The term "single-viscosity type" as used herein refers to commercially available hydroxypropyl methylcelluloses whose commercial names represent the respective viscosity types. Examples of mono-viscosity hydroxymethyl cellulose suitable for use in this invention include number average molecular, t850QO-9
Methocel Premium, a 4000 CPS viscosity polymer, contains 4M% A4M, E4M and F (24
) 4M (Dow Chemical Co., USA) and Methocel K15M made of a 15,000 cps viscosity polymer with a number average molecular weight of 120,000-130,000.

Other suitable polymers include viscosity grades 4000, 8000'& 15000, commercially available from Shin-Etsu (Japan).
Includes Metroose 5QSH165SH2 and 9QSH. Particularly preferred hydroxypropyl methylcelluloses are Methocel 4M Premium and Methocel K15.
M premium de Ruru.

The side-release tablets of this invention provide full therapeutic blood levels of naproxen or naproxen sodium over at least 24 hours and are therefore suitable for once-daily administration. Fluctuations in blood levels in multiple dose therapy regimens are reduced by the tablets of the invention, resulting in a ratio of average peak plasma concentration to beam plasma level of 2:1 or less.

In the present invention, when the word "about" is used with respect to a number average molecular weight, it indicates that the actual number average molecular weight can vary upward or downward within a range of 10% or less from the indicated value.

In addition, the words [J, -, U] in this invention refer to naproxen, nano-loxen sodium, lubricants, and other pharmaceutically acceptable excipients that may be included as desired in the tablets. When used in relation to the term, it indicates that the critical component amount can vary up or down by up to 10% relative to the indicated amount.

The following examples are illustrative of the invention and are not intended to limit the scope of the invention.

(Formulation A) Tablets were manufactured from the following ingredients.

1, U.S. Pharmacopoeia Naproki 3555 750°0sen 2, U.S. Pharmacopoeia Hydroki 356 75.1 Cypropyl Methyl Cellulone 2208. 15000 cps (Methocel K15M Premium) 3, US National Formulary 7 40 B, 4 Magnesium Tearate 4, USP Deionized 1896./Water Total Weight 0.83F/Tablet 2, Extended Release Cabroxen Tablets (750 Da) (Formulation B) Tablets were manufactured from the following ingredients.

1, US Pharmacopoeia Naproki 3402 750.0 sen 2, Hydroxypropyl 179 39.5 Methylcellulone 2 208.15000 cps (Methocel 1 5M Premium) 3, US National Formulary 38 8.4C27) Magnesium Thearate 4 , US Trade Union Deionized 1004 Total water weight 0.80'! /Tablet* Removed during the manufacturing process.

Preparations A and B were blended and tableted as follows.

Naproxen and Methocel K15M were mixed well and granulated using purified water. Heat the granules in an oven at 50℃ for 16 minutes.
Time tray dried, passed through a hammer mill equipped with an 18 gauge NuClean, and then mixed thoroughly with the magnesium stearate. The resulting homogeneous matrix material was compressed into tablets of uniform weight and size. Tablets of Formulation A have a load of 3000 lbs. Tablets of Formulation B have a load of 40 lbs.
Compressed at 1,000 lbs.

Example 3 Quantification of blood levels of sinaproxen was performed over 48 hours after administration of a single dose of 2 and B (*upstream 1 and 2) in a controlled release formulation. The control standard (28) was 2 tablets of Nabrosin™ 375, a non-controlled release formulation of naproxen. 6 healthy 2
Male volunteers aged 1-35 years were selected for the study. Participants were prohibited from using hypnotics, sedatives, antihistamines, or other enzyme-inducing drugs during the study and for one month prior. In addition, pharmaceutical alcohol, including over-the-counter drugs, is prohibited during or 72 hours before the trial begins.

The research was conducted as follows.

On each day of the 3-day dosing, which was administered at weekly intervals, the participants were administered a single dose of the drug formulation at 8:00 AM after fasting. Participants were randomly selected and each participant received one full dose of each formulation.
I took it one time at a time. Participants remained destitute at the reeds where a 4th hour blood sample was collected.

Before throwing stones and after throwing them 0.5.1.2.3.4゜6.8
．． At 10, 12, 14, 16, 20, 24 and 36, 48 hours, whole blood 10- was collected into heparinized evacuated tubes. The plasma was separated and frozen for later determination of naproxen plasma levels by HPLC (high performance adult chromatography). All plasma levels quantified for formulations A and B and the control Naprosyn tablets (formulation C) are illustrated in FIG.

Example 4 Misaki controlled release naproxen sodium tablets (550~) Tablets were manufactured from the following ingredients.

1, USP Naproki 5500 550.0 Sensodium 2, USP Hydroki 412.5 41.25 Dipropyl Methyl Cellulose 2208. 15,000 cps (Methocel K15M Bremium) 3, US Pharmacopoeia Talc 315 31.54, US National Formulary Magnesilum Stearate 35 3.5 rQ1) 5, US Pharmacopoeia Deionized 2100 36.0 Water Umbrella Naproxen Sodium Water Use 15 M'e of water was thoroughly mixed with naproxen sodium and Methocel, and granulated using purified deionized water.

The granules were tray-dried for 12 hours at 50°C in the open.
It was passed slowly through a hammer mill equipped with a gauge Nuclean and then thoroughly mixed with the talc 2 and magnesium stearate. Loading the resulting homogeneous matrix material 3
Tablets of uniform weight and size were compressed using a 500 pound press.

Example 5 After multiple administrations of controlled-release naproxen 75019 tablets (Formulation B of Example 2) every 24 hours and Naproxen (375”lf) tablets under the trade name Naprosyn every 12 hours, the mean of naproxen Plasma levels were quantified. Twelve healthy male volunteers aged 21-35 years were selected for the study. Participants were not prescribed hypnotics, sedatives, or antihistamines for 2 months during and 1 month prior to the study. Also, the use of other enzyme-inducing drugs was prohibited.Medications, including any over-the-counter drugs, or alcohol were prohibited during the study period.
It was forbidden two hours ago.

The test was conducted using a two-fold cross-validation method. 5 doses of test drug to each subject
It was administered over a period of days. According to a randomization schedule - participants were administered one of the study drugs (either controlled-release 750 tablets of Formulation B or 375 tablets of the brand name Naprosyn) at 9:00 a.m. after an overnight fast; . At 9:00 p.m., a second dose of Naprosyn tablets was administered to subjects receiving the control formulation Su7"oSyn375. Participants received the same daily dose of the drug for a total of five days. They were administered at the same time.

Every day, just before administration at 9:00 p.m., take a blood sample! r collected from participants. Morning blood samples on day 5 were taken after -night fasting. Thereafter, blood samples were collected at 9 am on the 5th day.
1.2.4.6.8°10.12.14.1 after administration of minutes
Harvested at 6.18.20.22 and 24 hours. The naproxen in the sample was quantified (32) and the average plasma naproxen concentrations obtained with the controlled release tablets (line B) and the non-controlled release Naprosyn tablets (line C) are shown in FIG.

The results of this multiple dose study showed that 750 liters of nazoloxene
The bioavailability of naproxen by one [i1i] daily administration of the controlled-release tablet (formulation B) containing Naprosyn 3
It was shown to be equivalent to that obtained by administering 75η tablets twice a day. The average peak-to-trough ratio of plasma levels obtained with the once-daily dosing of Formulation B tablets was 1.6:1, whereas the peak-to-trough ratio of plasma levels obtained with the 12-hourly dosing of Naprosyn 375 tablets was 1.6:1. The valley ratio was 1.9:1.

Example 6 24 controlled release naproxen 1000 tablets with the following composition:
Trade name Nazorosin 500 for hourly dosing and as standard
Quantification of mean plasma levels of naproxen was performed after multiple administrations of ``'P tablets administered every 12 hours.

1. Naproxen 1000.02, Hydroxypro 53.24 Pyl Methylcellulose 22 08. 3. U.S. National Drug Formulary Nutea! J 10.65 Magnesium Phosphate 4, FD&C Yellow 6 0.85 No. 5, USP Deionized Water Adequate Total Weight 1.07 F/tablet 14 healthy male volunteers aged 21-35 years tested. selected for. ? ! i! Experimenters were prohibited from using hypnotics, sedatives, antihistamines, or other enzyme-inducing drugs for 2 months during and 1 month prior to the study. Medications, including any over-the-counter drugs, or alcohol were not allowed during the study period.
Forbidden before time.

The test consisted of two 5-day washout periods between each treatment period;
A two-fold cross-validation method was used. - At the first appointment at 9:00 a.m. after an overnight fast, participants were given one of the study drugs (controlled-release 1
000"f tablets or 500" nabrosin tablets) were administered.The order of drug administration was randomized.9:00 p.m.
500 min to those who were administered the control formulation Naprosyn 50C1.
A second dose of mynaprosyn tablets was administered. Nazoloxene plasma levels were measured for 48 hours after the first study drug administration. Participants then continued to receive study drug for a total of 5 days, with a complete plasma picture taken on day 7.

Blood samples were collected from each participant each morning immediately prior to dosing. Immediately before administration on days 1 and 7, and thereafter, 1°2.4.6.
8.10.12.13.14.16゜18.20,22
．． Blood samples were collected from each participant at 24, 36 and 48 hours. Participants self-absorbed for 4 hours and blood samples were collected. Nuff.

Measure the plasma level of loxene and obtain 1tilJ
The average plasma concentrations achieved by dumping the dump-release tablets (iB) and Naprosyn tablets (line C) are shown in Figure 3 for day 1 and Figure 4 for day 7. Indicated.

The results of this multiple dose study showed that 1000"l of controlled-release tablets were administered every 24 hours and absorbed (35).
07"S"k was administered and absorbed. For the controlled release tablet 1000”f, the plasma level peak-to-trough ratio is 1.8:1;
For Naprosyn Tablets 500, the peak to trough ratio of plasma levels was 2.6:1.

[Brief explanation of the drawings] Figure 1 shows the test results of Example 3, where A is the tablet obtained in Example 1, B is the tablet obtained in Example 2, and C is the commercial product (trade name Naprosyn). A curve showing the concentration of naproxen in plasma after one administration of Figure 2 shows the test results of Example 5, B shows the result of once-daily administration of the tablet obtained in Example 2, and C shows the result of twice-daily administration of the commercially available product (trade name Naprosyn). A curve showing the plasma naproxen concentration on the 5th day is shown. 3. 2 and 4 respectively show the first case of Example 6.
Showing the plasma naproxen concentration on day 7 and day 7,
B shows the curve obtained with once-daily dosing of a controlled-release tablet; C shows the curve obtained with twice-daily dosing of the commercial product (trade name Naprosyn). Patent Applicant: Syntex Pharmaceuticals International, Inc.

Claims (1)

Claims: (1) A controlled release tablet for oral administration once a day containing about 500-1200 μg of naproxen or naproxen sodium, said tablet containing about 500 μg of naproxen sodium. about 4-9% by weight of hydroxypropyl methylcellulose having a number average molecular weight ranging from about 130,000 to about 81-96% naproxen or naproxen sodium
Homogeneous IJ socks are comprised of 0.1% to about 2% by weight of a pharmaceutically acceptable lubricant and 0% to about 8% by weight of a pharmaceutically acceptable excipient. Controlled-release tablets. (2) The controlled-release tablet according to claim 1, characterized by naproxen. (3) Hydroxypropyl methylcellulose is about 12
having a number average molecular weight of 0,000 to 130,000;
Controlled release tablet according to claim 2. (4) A patent consisting of about 5% by weight of hydroxypropyl methylcellulose, about 92-9% by weight of naproxen, 0.1 to about 2% by weight of magnesium stearate, and 0 to about 1% by weight of a pharmaceutically acceptable colorant. Controlled release tablet according to claim 3. (5) The controlled release tablet according to claim 4, wherein the amount of naproxen is 500 g. (6) The controlled release tablet according to claim 5, characterized in that it contains about 0.01-0.05% by weight of FD&C Yellow No. 6. (7) The controlled release tablet according to claim 4, wherein the amount of naproxen is 750 to 750. (8) The controlled release tablet according to claim 7, characterized in that it contains about 0.01-0.05% by weight of FD&C Yellow No. 6. (9) The controlled release tablet according to claim 4, wherein the amount of naproxen is 1,000 to 1,000. (FD&C Yellow No. 6 approx. 0.01-0
Controlled release tablet according to claim 9, characterized in that it contains 0.05% by weight. (11) Hydroxypropyl methylcellulose is about 1
Controlled release tablet according to claim 1, having a number average molecular weight of 20,000 to 130,000. (Foundation) Hydroxypropyl methylcellulose approximately 5% by weight, naproxen or naproxen sodium approximately 8% by weight
5-95% by weight, 0.1 to about 2% by weight of lubricant, and 0 to about 8% by weight of other pharmaceutically acceptable excipients.
12. A controlled release tablet according to claim 11, comprising: (13) Claim 12, wherein the amount of naproxen or naproxen sodium is about 500-550 ■
Controlled release tablets as described in Section. (14) Claim 12, wherein the amount of naproxen or naproxen sodium is about 750-80°.
Controlled release tablets as described in Section. (15) The controlled release tablet according to claim 12, wherein the amount of naproxen or naproxen sodium is about 1000-1100 μ. (16) About 9% by weight of hydroxypropyl methylcellulose, about 8% by weight of naproxen or naproxen sodium
1-91% by weight, 0.1 to about 2% by weight of lubricants, and 0 to about 8% by weight of other pharmaceutically acceptable excipients.
12. A controlled release tablet according to claim 11, comprising: (17) Claim 16, wherein the amount of naproxen or naproxen sodium is about 500-550.
Controlled release tablets as described in Section. (18) Claim 1, wherein the amount of naproxen or naproxen sodium is about 750-800 mDa.
Controlled release tablet according to item 6. C19) The controlled release tablet of claim 16, wherein the amount of naproxen or naproxen sodium is from about 1000-1100. (2D) Hydroxypropyl methylcellulose is about 8
Controlled release tablet according to claim 1, having a number average molecular weight of 5,000 to 95,000. (21) Hydroxypropyl methylcellulose about 7-
9% by weight, about 81-93% by weight naproxen or naproxen sodium, 0.1 to about 2% by weight lubricant,
21. The controlled release side tablet of claim 20, comprising O to about 8% of other pharmaceutically acceptable excipients. (22) Claim 21, wherein the amount of naproxen or naproxen sodium is about 500-550η.
Controlled release tablets as described in Section. (23) Claim 21, wherein the amount of naproxen or naproxen sodium is about 750-800.
Controlled release tablets as described in Section. (24) The controlled release tablet of claim 21, wherein the amount of naproxen or naproxen sodium is about 1000-1100. (25) The controlled-release tablet according to claim 1, characterized by naproxen sodium. (26) Number average molecular weight is about 120,000-130,000
Hydroxypropyl methylcellulose in the range of about 6-8
wt%, naproxen sodium about 82-90 wt%,
0.1 to about 2% by weight of a lubricant, about 4-6% by weight of a pharmaceutically acceptable glident, and 0 to about 2% by weight of other pharmaceutically acceptable excipients. Controlled release tablet according to item 25. (27) -)-The amount of proxen sodium is about 550
27. The controlled release tablet of claim 26, which is . (28) The controlled release tablet of claim 26, wherein the amount of naproxen sodium is about 1,100 to about 1,100. (29) The controlled-release tablet according to claim 1, wherein the lubricant is magnesium stearate. (30) A controlled release tablet according to claim 2, characterized in that hydroxypropyl methylcellulose constitutes about 4-6% by weight of the tablet. (31) The controlled release tablet according to claim 2, wherein the amount of naproxen is about 500 to about 500. (32) The controlled release tablet of claim 2, wherein the amount of naproxen is about 750 mg. (33) The controlled release tablet according to claim 2, wherein the amount of naproxen is about 1,000 to about 1,000.