HK1129590B - Multiple unit type sustained release oral formulation and process for the preparation thereof - Google Patents

Description

Multi-unit type sustained release oral preparation and method for preparing the same

Technical Field

The present invention relates to a sustained-release oral preparation, and more particularly, to a multiple unit type sustained-release oral preparation (multiple unit type sustained release formulation) containing both a sustained-release portion and a rapid-release portion.

Background

The advantages of sustained release formulations, which are widely known in the pharmaceutical field, are generally known. Among these advantages are that the concentration of the drug in the blood can be maintained at a desired level for a relatively long time, so that the frequency of administration required to achieve the same effect as conventional administration can be reduced, and also, as a result, patient compliance with the drug can be enhanced. Moreover, where a particular medication requires that the medication be administered in a sequential manner such that a good therapeutic effect may be expected, such medication may be administered by the patient following the prescribed regimen on a prescribed schedule, but there are many situations where it is often difficult to achieve the desired therapeutic effect due to patient non-compliance. Thus, the development of sustained release formulations that can constantly release the drug, which otherwise should be repeatedly administered several times a day to maintain an effective plasma concentration of the drug, may help to simplify treatment and reduce or eliminate the risk of inappropriate administration. In the case of non-steroidal anti-inflammatory drugs, which are currently subject to undesirable long-term administration, the need for such formulations is currently pressing.

To minimize the effects of missed doses due to patient compliance, and to maintain therapeutic blood levels of the drug, a number of techniques have been used to provide controlled and extended release formulations. Drugs administered in conventional simple tablet or capsule formulations tend to show a rate of such drugs reaching body fluids which is initially very high and then decreases dramatically. Such patterns result in many drugs exhibiting temporary excess drug blood concentrations, and therapeutically insufficient subsequent drug concentrations. These problems limit the clinical use of the formulation. This mode of delivery was improved in the 70's of the 20 th century by the introduction of a variety of controlled delivery systems. These systems, which provide relatively constant controlled drug delivery, allow excessive blood concentrations of the drug and inadequate maintenance of blood concentrations of the drug to be avoided. This technique results in the delivery of effective drugs with reduced side effects and reduced frequency of administration.

More specifically, WO98/01117 discloses sustained release formulations comprising a sustained release carrier which can release a non-steroidal anti-inflammatory drug over a desired sustained release period (12 to 24 hours), and a sustained release excipient sufficient to prepare such sustained release formulations.

Such sustained release formulations that control the dissolution rate of the active ingredient can be divided into single unit type formulations and multiple unit type formulations. A multiple unit type formulation is a formulation having two or more units which coexist in a single formulation and differ from each other in terms of drug release rate, as opposed to a single unit type formulation having one unit. The multiple unit type formulation may be referred to as a sustained release formulation further developed from a single unit type formulation because the multiple unit type formulation has excellent properties such as less fluctuation in absorption of active ingredients, good reproducibility of dissolution of a drug, and applicability of two or more active ingredients, compared to a single unit type formulation.

In particular, in the case of non-steroidal anti-inflammatory drugs, since the properties of these drugs are required to exhibit rapid efficacy performance, the drugs are required to develop efficacy immediately after administration and to be able to maintain the effect for 24 hours. Therefore, a multiple unit type sustained release formulation capable of simultaneously exhibiting a rapid release property and a sustained release property is required.

Zaltoprofen (zaltoprofen) is a nonsteroidal anti-inflammatory drug which has excellent effects on chronic inflammation after surgery or trauma. Zaltoprofen is generally required to be administered three times a day, in an adult dose of about 80 mg. Therefore, in order to improve convenience and administration compliance of patients and reduce gastrointestinal side effects, once-daily administration preparations that enable once-daily administration are desired. However, there have been no reports to date on sustained release formulations developed specifically for zaltoprofen.

Disclosure of Invention

Technical problem

It is therefore an object of the present invention to provide a multiple unit type sustained release formulation which helps to control the release of the active ingredient.

It is another object of the present invention to provide a method for preparing a multiple unit type sustained release formulation which helps control the release of an active ingredient.

Technical scheme

In one aspect to achieve the above objects, the present invention provides a multiple unit type controlled release oral formulation comprising:

sustained release pellets (pellets) formed of particles containing an active ingredient and a water-insoluble polymer, the particles being coated with a sustained release matrix material; and

quick release granules containing an active ingredient. Such sustained release oral formulations may be in the form of tablets or capsules.

The granules constituting the sustained-release pellet may contain 5 to 30 parts by weight of the water-insoluble polymer with respect to 100 parts by weight of the active ingredient in the sustained-release pellet. Furthermore, the granules may be coated with 5 to 40 parts by weight of the sustained-release matrix material with respect to 100 parts by weight of the active ingredient in the sustained-release pellets to form the sustained-release pellets.

The ratio of the active ingredient contained in the sustained-release pellets to the active ingredient contained in the fast-release granules of the sustained-release preparation may be 1: 1 to 100: 1, but is not limited thereto.

The water-insoluble polymer constituting the particles may be selected from: water-insoluble cellulose or its derivatives, polymethacrylates, and mixtures of two or more types of polymethacrylates and polyalkylacrylates, but are not limited thereto. Among these water-insoluble polymers, ethyl cellulose is preferable, and more preferably, ethyl cellulose having a viscosity of 7 to 14cps may be used.

For the sustained-release matrix material used to coat the particles, a water-insoluble polymer may be used, and ethylcellulose is particularly preferred.

The sustained-release pellets containing the granules coated with the sustained-release matrix material preferably have a diameter of 0.05 to 2 mm.

For the active ingredient of the sustained release formulation, any drug requiring sustained release characteristics can be used, and in particular, zaltoprofen, a nonsteroidal anti-inflammatory drug, can be used.

In another aspect, the present invention provides a method for preparing a multiple unit type sustained release formulation, and in particular, a method for preparing a multiple unit type sustained release tablet, comprising the steps of:

preparing particles comprising an active ingredient and a water-insoluble polymer;

coating the granules with a sustained-release matrix material to prepare sustained-release pellets;

preparing a fast-release granule containing an active ingredient; and

the sustained release pellets and the fast release granules are mixed with pharmaceutically acceptable additives and the mixture is tableted.

The present invention also provides a method for preparing a multiple unit type sustained release capsule comprising the steps of:

preparing particles comprising an active ingredient and a water-insoluble polymer;

coating the granules with a sustained-release matrix material to prepare sustained-release pellets;

preparing a fast-release granule containing an active ingredient; and

hard capsules were filled with sustained release pellets and fast release granules.

Drawings

Fig. 1 is a graph showing the results of a drug dissolution test using a multiple unit type sustained release coated tablet containing 240mg of zaltoprofen, prepared according to example 3 of the present invention, compared with a Soleton tablet containing 80mg of zaltoprofen (CJ corp., ROK), which is commercially available as a control.

FIG. 2 is a graph showing the mean drug plasma concentration curves over time obtained by once administering a daily dose of 240mg of beagle dogs using a multiple unit type sustained release coated tablet containing 240mg of zaltoprofen, prepared according to example 3 of the present invention, compared with a Soleton tablet containing 80mg of zaltoprofen (CJ Corp., S.Korea) commercially available as a control.

Detailed Description

Hereinafter, the present invention will be described in more detail.

The present invention relates to a polycell sustained release. The inventors of the present invention have studied the following pharmaceutical preparations: the drug requires a rapid release of an active ingredient for rapid exhibition of efficacy, and also requires a sustained release for once-a-day administration, particularly for the nonsteroidal anti-inflammatory drug zaltoprofen, and as a result, it was found that a formulation promoting initial rapid drug release and sustained control of drug release can be obtained by introducing into a single formulation a rapid release granule containing an active ingredient for rapid drug release, and a sustained release pellet formed from a granule containing a water-insoluble polymer and an active ingredient, the granule being coated with a sustained release matrix material for sustained drug release, thereby completing the present invention.

Accordingly, the present invention provides a sustained release formulation which is a multiple unit type sustained release oral formulation comprising:

sustained-release pellets formed from granules containing an active ingredient and a water-insoluble polymer, the granules being coated with a sustained-release matrix material; and

quick release granules containing an active ingredient. Such sustained-release oral formulations may particularly be in the form of tablets or capsules, but the present invention is not limited thereto.

The granules constituting the sustained-release pellets contain an active ingredient and a water-insoluble polymer, and are prepared into such forms by conventional methods for preparing granules: wherein the active ingredient is uniformly dispersed in the water-insoluble polymer. The water-insoluble polymer constituting these particles can be used to control the manner of sustained release of the active ingredient by controlling the type of water-insoluble polymer and the mixing ratio of the water-insoluble polymer to the active ingredient, taking into account the solubility of the active ingredient in water.

The mixing ratio of the active ingredient forming the granules and the water-insoluble polymer may be suitably selected from a range capable of controlling the dissolution of the active ingredient, but preferably, the water-insoluble polymer may be present in an amount ranging from 5 to 30 parts by weight, more preferably, from 10 to 20 parts by weight, relative to 100 parts by weight of the active ingredient in the sustained-release pellets.

The water-insoluble polymer constituting such particles may be any water-insoluble polymer known to be suitable for use in the pharmaceutical field, and in particular, may be selected from: water-insoluble cellulose or derivatives thereof, polymethacrylates, and mixtures of two or more types of polymethacrylates and polyalkylacrylates. The water-insoluble cellulose or a derivative thereof can be exemplified by cellulose acetate, cellulose acetate phthalate, hydroxypropylcellulose phthalate (hydroxypropyl methyl cellulose phthalate), ethyl cellulose, and the like. The mixture of two or more types of polymethacrylates and polyalkylacrylates may be exemplified by a mixture of polymethacrylates and polymethylmethacrylate in a 1: 1 ratio, or a mixture comprising polyethylacrylate, polymethylmethacrylate, and polytrimethylaminoethylmethacrylate chloride in a 1: 2: 0.1 or 1: 2: 0.2 ratio. These water-insoluble polymers may be used alone or in combination. For the water-insoluble polymer, ethyl cellulose may be preferably used, and ethyl cellulose having a viscosity of 7 to 14cps may be most preferably used.

The release of the active ingredient may be further controlled when the granules are coated with a sustained-release matrix material to form sustained-release pellets. When such a coating of the sustained-release matrix material is additionally introduced, the control of the release of the active ingredient can be further promoted, and the release of the active ingredient contained in the sustained-release pellets can be controlled over a prolonged period of time.

The amount of the sustained-release matrix material used in the coated granule may be suitably selected from a range capable of controlling dissolution of the active ingredient, but the sustained-release matrix material may be used in an amount ranging from 5 to 40 parts by weight, preferably from 10 to 20 parts by weight, relative to 100 parts by weight of the active ingredient in the sustained-release pellet. The above-mentioned water-insoluble polymer can be used as a sustained-release matrix material for use in preparing pellets, and ethylcellulose can be preferably used.

The sustained-release pellets formed by coating the granules with the sustained-release matrix material preferably have a granule size in the range of 0.05 to 2mm, which is suitable for formulation into a form of oral preparation, particularly a tablet or capsule.

The fast-release granules containing the active ingredient constitute another part of the multiple unit type sustained release formulation according to the present invention, which is intended to rapidly release a part of the drug after administration of the sustained release formulation, thereby minimizing the time required for the drug to reach an effective blood concentration. The fast-release particles may be prepared by conventional methods known in the art for preparing fast-release particles.

The active ingredient that can be used in the multiple unit type sustained release oral formulation may be any drug that requires sustained release after oral administration in vivo. By a drug requiring sustained release is meant a drug with short-term activity that needs to be administered several times a day to maintain a therapeutically effective concentration. Examples of such drugs include antidiabetic drugs, antibiotics, angiotensin converting enzyme inhibitors, non-steroidal anti-inflammatory drugs, antihyperlipidemic drugs, cardiovascular drugs, anti-asthmatic drugs, anti-depressive drugs, antihistamines, etc., and in particular, the non-steroidal anti-inflammatory drug zaltoprofen may be used in a sustained release formulation according to the present invention.

The sustained-release preparation of the present invention contains the same active ingredient in the fast-release granules as well as the sustained-release pellets, so that the sustained-release preparation allows, as a main object, the fast release as well as the sustained release of the drug, so as to maintain both the fast and sustained activity of the drug at an effective blood concentration of the drug even by once-a-day administration. However, it is also possible to use different drugs for the fast-release granules and the sustained-release pellets, so that a combined drug effect can be obtained by administering a single formulation.

The multiple unit type sustained release preparation may be specifically prepared as a sustained release preparation in the form of a tablet or capsule.

The multiple unit type sustained release tablet can be prepared by a method comprising:

preparing particles comprising an active ingredient and a water-insoluble polymer;

coating the granules with a sustained-release matrix material to prepare sustained-release pellets;

preparing a fast-release granule containing an active ingredient; and

the sustained-release pellets and the fast-release granules are mixed with pharmaceutically acceptable additives and the mixture is tableted.

In the preparation of the particles, first, the water-insoluble polymer is dissolved in an organic solvent alone or dispersed in distilled water to prepare a solution or dispersion of the water-insoluble polymer, and then the particles are prepared from the solution or dispersion by a conventional method for preparing particles. As the method for preparing the granules, for example, a method of wet granulation or a method of dry granulation may be used. For the wet granulation method, a method using a fluidized bed granulator or a method using a high speed mixer may be applied, and for the dry granulation method, another method using band granulation using a roller compactor, a direct tableting method of a water-insoluble polymer raw material using an excipient for direct tableting, or the like is applied. In particular, in the case of using a fluidized bed granulator, which is sufficiently dried and preheated at an inlet temperature in the range of 60 to 85 ℃ and an outlet temperature of 30 to 65 ℃, the granules may be prepared by absorbing a solution of a water-insoluble polymer onto zaltoprofen at a rate of 300 mL/hr to 1500 mL/hr. The most suitable spraying conditions include an input temperature of 65-75 deg.C (input temperature), and a discharge temperature of 30 to 45 deg.C (exhaust temperature), and a mixed solution input of 720 mL/hr.

In order to apply the sustained-release matrix material to the particles containing the active ingredient and the water-insoluble polymer, a solution of the water-insoluble polymer may be prepared as the sustained-release matrix material, and may be used as the sustained-release coating according to a conventional method of coating the particles. The solution of the water-insoluble polymer used as such a sustained-release matrix material can also be applied by dissolving the water-insoluble polymer in an organic solvent or distilled water alone, or by dissolving or dispersing the water-insoluble polymer in an organic solvent or distilled water together with an organic acid, in the same manner as the preparation of the solution or dispersion of the water-insoluble polymer applied in the preparation of the particles. Such an aqueous solution of a sustained-release matrix material may further comprise a lubricant selected from talc, titanium oxide, light anhydrous silicic acid (light anhydrous silicic acid) and the like, while the aqueous dispersion may further comprise pharmaceutically acceptable additives, for example, a plasticizer such as polyethylene glycol or triacetin. For the particle coating method, a method using a fluidized bed granulator may be particularly used. Here, the sustained-release property of the drug can be further controlled by the coating thickness of the sustained-release matrix material thus formed.

The fast-release granules containing the active ingredient may be prepared by a granulation process selected from: a method using a fluid granulator according to the wet granulation method and containing additives which are pharmaceutically acceptable excipients, such as conventionally used binders and disintegrants; and a method using a high-speed mixer.

The sustained-release tablet according to the present invention can be prepared as follows: mixing the sustained-release pellets and the fast-release granules in a predetermined ratio, adding at least one pharmaceutical additive selected from excipients, lubricants, colorants, etc. conventionally used in the production of tablets, and tableting the mixture. In such sustained-release preparations, the ratio of the active ingredient contained in the sustained-release pellets to the active ingredient contained in the rapid-release granules can be adjusted to a range of 1: 1 to 100: 1, preferably, 7: 3 to 9: 1.

The excipients may preferably be selected from: lactose, microcrystalline cellulose, corn starch, potato starch, wheat starch, sucrose, D-mannitol, precipitated calcium carbonate, dextrin, pregelatinized starch, and combinations thereof. The content of the excipient may be 10 to 90 parts by weight, based on the total weight of the tablet.

The binder may preferably be selected from: polyvinylpyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose for direct tableting, hydroxypropyl methylcellulose, dextrin, gelatin, methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, paste (paste), gum arabic and combinations thereof, and it may be used in an amount of 2 to 40 parts by weight, based on the total weight of the tablet.

The disintegrant may preferably be selected from: sodium starch glycolate, crospovidone, croscarmellose sodium, low substituted hydroxypropylcellulose, starch, calcium carboxymethylcellulose, and combinations thereof, and the disintegrant may be included in an amount of 0.1 to 32 parts by weight, based on the total weight of the tablet composition.

The lubricant may preferably be selected from: magnesium stearate, talc, light anhydrous silicic acid, and combinations thereof, and the lubricant may be included in an amount of 0.1 to 20 parts by weight, based on the total weight of the tablet.

As the colorant, at least one selected from the following may be contained in the tablet: titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, aluminum lakes (aluminum lakes) such as blue No. 1 aluminum lake, red No. 40 aluminum lake, and the like.

The sustained-release tablet thus prepared may be further subjected to a film-coating process. For the film coating agent, enteric or non-enteric film coating agents may be used, and the enteric film coating agent may be Cellulose Acetate Phthalate (CAP), polyvinyl acetate phthalate (PVAP), methacrylate polymer (Eudragit L, S), etc., and the non-enteric film coating agent may be hydroxypropyl cellulose (HPC), Methyl Cellulose (MC), Ethyl Cellulose (EC), hydroxypropyl methyl cellulose (HPMC), povidone (PVP), polyvinyl alcohol (PVA), Cellulose Acetate (CA), shellac, etc. Such tablet coating methods can be carried out by, for example, pan coating (pan coating) method, fluidized bed coating method, compression coating method (compression coating) and the like.

In the above-mentioned multiple unit type sustained release oral preparation, a capsule can be prepared by mixing sustained release pellets prepared in the same manner as tablet preparation with a rapid release capsule and filling a hard capsule with the resulting mixture. Filling of the capsules can be carried out by conventional methods such as fluidizing the pellets under pressure to fill the hard capsules, by free-fall filling the hard capsules, and the like.

The amount of the sustained-release preparation according to the present invention to be administered to a human body may be appropriately selected depending on the absorption rate in vivo, inactivation rate, excretion rate, age, sex, and condition of a patient, severity of disease, and the like.

Examples

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the present invention is not intended to be limited by these examples.

Example 1

A. Preparation of Water-insoluble Polymer solutions

100g of ethylcellulose, a water-insoluble polymer having a viscosity of 14cps, was added to 1000g of an 80% ethanol aqueous solution, and then the mixture was stirred with a mechanical mixer at 1000rpm for 30 to 60 minutes to prepare a solution of the water-insoluble polymer.

B. Preparation of particles containing zaltoprofen and a water-insoluble polymer

The fluid bed granulator was thoroughly dried and preheated at an inlet temperature of 65 ℃ and an outlet temperature of 30 ℃ and the resulting solution of the water insoluble polymer ethylcellulose was subsequently absorbed onto 500g of zaltoprofen at an input rate of 720 mL/h, producing 600g of granules.

C. Preparation of coating solution of sustained-release matrix material

75g of ethylcellulose, a sustained-release matrix material having a viscosity of 14cps, was added to 750g of an 80% ethanol aqueous solution, and then the mixture was stirred with a mechanical mixer at 1000rpm for 30 to 60 minutes. Thereafter, 15g of talc were added and mixed therewith.

D. Preparation of sustained Release pellets

600g of the granules prepared in step B above were sprayed with a fluidized granulator and the sustained-release material coating solution prepared in step C above was sprayed at an input rate of 720 mL/hr to produce 690g of sustained-release pellets having a diameter in the range of 0.05 to 1.5 mm.

E. Preparation of fast release granules

12g of a polyvinylpyrrolidone binder having a molecular weight of 30,000 to 50,000kg/mol was mixed with 60g of a 50% ethanol aqueous solution, and the binder was dissolved therein while being stirred at a rate of 600rpm with a mechanical mixer to prepare a binder solution.

72g of zaltoprofen, 90g of microcrystalline cellulose and 60g of sodium starch gluconate (sodium starch gluconate) are mixed, and then when the previously prepared binder solution is introduced into a high-speed mixer, fast-release granules of zaltoprofen are prepared. The operating conditions of the high speed mixer are shown in table 1 below.

TABLE 1

	Mincer (rpm)	Beater (rpm)	Time (minutes)
				Mixing (mixing)	1000	150	10

Mixing	1500	200	15
				Granulating	1200	200	15

After the granules were prepared under the above conditions, the granules were dried until the weight loss at the time of drying at 40 ℃ was 3% or less, followed by sieving with a 25-35 mesh-sized shaker.

F. Preparation of multiple unit type sustained release tablet

Sustained release tablets are prepared by direct compression methods. 298.08g of the zaltoprofen sustained release pellets prepared above were mixed with 78g of the fast release granules prepared in step E, and 2.92g of magnesium stearate, and the mixture was then formed into 379mg tablets having a hardness of 7 to 12 Kp.

Example 2: preparation of multiple unit type sustained release capsules

298.08g of sustained-release pellets of zaltoprofen prepared in steps D and E of example 1, 78g of the fast-release granules and 2.92g of magnesium stearate were co-filled into 379mg of No. 0 hard capsules by a free-fall method to prepare sustained-release capsules.

Example 3: preparation of multiple unit type sustained release coated tablets

A. Preparation of multiple unit type sustained release tablet

The sustained-release tablet was prepared by the same method as in example 1.

B. Film coating of sustained release tablets

20g of coating reagent, OpadryAMB (PVA; Colorcon, Inc.) was suspended in 200g of distilled water to prepare a coating suspension, and the zaltoprofen sustained release tablet prepared in step A was injected into a coating pan (Hi-coater). The dried tablets in the coating pan are maintained at an intake air temperature of 75 to 85 c and an exhaust air temperature of about 35 to 45 c. The coating suspension is sprayed onto the dried tablets with a pneumatic spraying device, followed by air supply for an additional 30 to 40 minutes to dry the coated tablets. The amount of Opadry (PVA; Colorcon, Inc.) coating material on the thus obtained tablets was 2.11% based on the total weight of the tablets.

The formulations of the formulations prepared in examples 1 to 3 are shown in table 2 below.

TABLE 2

Experimental examples: dissolution test and absorption test

A. In vitro testing

Dissolution testing was performed on the multiple unit type sustained release tablets prepared in example 3 above. Dissolution Test procedure was performed according to dissolution Test No. 2 in korean pharmacopoeia General Test Methods, and the Test was performed on the above-prepared tablets and capsules at 100rpm/min using water or a buffer solution of ph7.8 as an eluent for 12 hours. At 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, and 12 hours after the start of the dissolution test, an amount of 5ml of the eluate was taken each time, and filtered. The filtrate was used as a test solution in analysis using high performance liquid chromatography. The commercially available product, Soleton (fast release formulation), was used as a control. The results are shown in FIG. 1.

Referring to fig. 1, the sustained release formulation of example 1 showed dissolution rates of 20 to 40% at 1 hour, 40 to 60% at 3 hours, and 80% or more at 12 hours. As can be seen from these results, the sustained-release formulation of the present invention is capable of initially releasing a relatively large amount of drug and sustainedly releasing the drug over a 12-hour period, and thus, is a formulation which shows efficacy immediately after administration and requires administration only once per day. Such a release profile is distinguished from the release profile of the control used, which is a commercially available fast release formulation SoletonIt showed 100% dissolution in a short time.

B. In vivo testing

Beagle dog (Marshall beijing, china, 13 months old, average body weight 11.5kg, male) was fasted for a full day before administration of the test material, and the zaltoprofen sustained release tablet prepared in example 3 above and the commercially available Soleton tablet were forcibly administered orally. After administration, 10mL of water was forced. The dosing regimen is shown in table 3.

TABLE 3

Administration set	Using substances	Sex	Number of animals	Animal reference number	Dosage (mg/animal)
						T1	1stExample 32nd-Soleton	Male sex	3	A-CD-F	240mg tablet/animal
T2	1st-Soleton2ndExample 3	Male sex	3	D-FA-C	240mg tablet/animal

Blood samples were taken from the test animals and sampled at 20 minutes, 40 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, and 30 hours after administration. Depending on the group composition, 1ml of blood was taken from the cephalic vein or jugular vein on the sampling schedule. The collected blood was filled in a container which had been treated with anticoagulant (EDTA) or heparin, and centrifuged at 13,000rpm for 3 minutes to separate and analyze plasma. When the separated plasma was not analyzed immediately, the plasma was stored in a refrigerator (-20 ℃) until the time of analysis.

The sample was pretreated by adding 100. mu.l of an internal standard solution (25. mu.l/ml) of diphenyloxazole (diphenyloxazole) to 200. mu.l of plasma, followed by adding 100. mu.l of 2M acetic acid and 1ml of dichloromethane thereto, and shaking the mixture for 40 seconds. The drug was removed from the plasma and analyzed by HPLC to generate a mean blood concentration profile as shown in figure 2. Also, the average blood concentration of all sustained-release pellets and the average blood concentration of all fast-release granules of the sustained-release formulation of example 3 were measured, and the results are shown in fig. 2.

Based on these blood concentration maps, common in vivo pharmacokinetic parameters such as maximum blood concentration (C) were calculated based on non-compartmental model (non-multivariate model) analysis_max) Time to maximum blood concentration (T)_max) The area under the concentration curve (AUC), etc., and the results are shown in table 4.

TABLE 4 zaltoprofen sustained release tablets and SoletonComparison of pharmacokinetic parameters of tablets

As can be seen from the results of the time-dependent change in blood concentration in fig. 2 and the pharmacokinetic parameters in table 4, the zaltoprofen sustained release tablet prepared in example 2 is more effective for use in vivo than the control Soleton tablet.

Industrial applications

As discussed above, according to the present invention, a sustained-release formulation can be provided which exhibits such a degree of sustained release: once daily administration makes administration convenient and patient compliance possible and exhibits a rapid release immediately after administration so that effective blood concentrations of the drug can be reached quickly. The sustained-release preparation can be usefully applied to cases where: where sustained release is required due to the nature of the drug and rapid onset of efficacy is required.

Claims (7)

1. A multiple unit type sustained release oral formulation comprising:

sustained release pellets formed from granules containing zaltoprofen and ethylcellulose, said granules being coated with ethylcellulose; and

a fast-release granule comprising zaltoprofen,

wherein the granules constituting the sustained-release pellets are characterized by containing ethylcellulose in an amount ranging from 5 to 30 parts by weight relative to 100 parts by weight of zaltoprofen in the sustained-release pellets, and

the sustained-release pellet is characterized in that it is coated with 5 to 40 parts by weight of ethylcellulose relative to 100 parts by weight of zaltoprofen in the sustained-release pellet.

2. The multiple unit type sustained release oral formulation of claim 1, which is in the form of a tablet or capsule.

3. The multiple unit type sustained release oral formulation according to claim 1, wherein the ratio of zaltoprofen contained in the sustained release pellets to zaltoprofen contained in the fast release granules is characterized in that it is from 1: 1 to 100: 1.

4. The multiple unit type sustained release oral formulation of claim 1, wherein the ethylcellulose is characterized in that it has a viscosity of 7 to 14 cps.

5. The multiple unit type sustained release oral formulation of claim 1, wherein the sustained release pellet is characterized in that it has a diameter of 0.05mm to 2 mm.

6. A method of making a multiple unit type sustained release tablet comprising the steps of:

preparing particles containing zaltoprofen and ethylcellulose;

coating the granules with ethyl cellulose to prepare sustained-release pellets;

preparing fast-release particles containing zaltoprofen; and

mixing the sustained-release pellets and the fast-release granules together with pharmaceutically acceptable additives and tabletting the mixture,

wherein the granules constituting the sustained-release pellets are characterized by containing ethylcellulose in an amount ranging from 5 to 30 parts by weight relative to 100 parts by weight of zaltoprofen in the sustained-release pellets, and

the sustained-release pellet is characterized in that it is coated with 5 to 40 parts by weight of ethylcellulose relative to 100 parts by weight of zaltoprofen in the sustained-release pellet.

7. A method of making a multiple unit type sustained release capsule comprising the steps of:

preparing particles containing zaltoprofen and ethylcellulose;

coating the granules with ethyl cellulose to prepare sustained-release pellets;

preparing fast-release particles containing zaltoprofen; and

filling the sustained-release pellets and the fast-release granules into a hard capsule,

wherein the granules constituting the sustained-release pellets are characterized by containing ethylcellulose in an amount ranging from 5 to 30 parts by weight relative to 100 parts by weight of zaltoprofen in the sustained-release pellets, and

the sustained-release pellet is characterized in that it is coated with 5 to 40 parts by weight of ethylcellulose relative to 100 parts by weight of zaltoprofen in the sustained-release pellet.