KR101811700B1 - Sustained Release Tablets Containing Levodropropizine and Manufacturing Method for the same - Google Patents

Abstract

The present invention relates to a levodoprofen sustained-release formulation comprising a slow-release layer comprising levodopropegin and a sustained-release layer comprising levodoprofen and a release-controlling polymer.

Description

Technical Field [0001] The present invention relates to levodoprofen-containing sustained release tablets,

The present invention relates to levodoprofen-containing sustained-release preparations which are used as an expectorant. More particularly, the present invention relates to levodoprofen-containing sustained-release preparations which allow the drug absorption to be delayed by controlling the drug release by mixing levodopropegin with a polymer compound.

Levodoprojipine inhibits c-fiber, a peripheral nerve involved in cough reflexes, and inhibits the inflammatory response, bronchoconstriction, airway hyperresponsiveness, vascular permeability, and cough reflex induced by neuropeptides at the c-fiber end There is an inhibiting effect.

At least 75% of levodoprodepizine is absorbed by oral administration, and the time to reach the peak plasma concentration is about 0.25-1 hours, followed by about 35% of the levodoprodepine in the body, and the excretion rate (half-life) is about 1 It is known to be about an hour.

Levodoprofen is currently in the form of a tablet developed and marketed, and 60 mg should be given once a day, three times a day.

In the case of commercially available levodoprojipine preparations, dissolution and absorption are carried out immediately upon taking, and there is no problem in expressing the pharmacological effect promptly. However, by maintaining the effective blood concentration of the drug for a long time, it is possible to reduce the amplitude of the blood concentration caused by frequent administration of the usual preparation, thereby reducing the side effect, and by reducing the frequency of administration, There is a growing need for sustained-release formulation of levodoprofen, which can eliminate the discomfort caused by taking it.

Korean Patent Laid-Open No. 10-2011-0113413 discloses a sustained-release pharmaceutical composition comprising levodopropegin as an active ingredient and a method for producing the same.

For slow release preparations of levodoprojin, the initial dissolution rate at a certain point in the two-phase, two-phase, and multi-phase formulations (the formulation consisting of immediate and extended layers), which simultaneously satisfy the initial rapid pharmacological activity and sustained efficacy, And it is important that the effective blood level of the drug is maintained constantly until 12 hours.

KR 2011-0113413 A

The present inventors have succeeded in achieving the above-mentioned object by simultaneously preparing a matrix-type sustained-release layer containing levodopropegin by high-viscosity hydroxypropylmethylcellulose and a tablet portion containing levodopaedin in an amount of one tablet for quick initial treatment .

Accordingly, an object of the present invention is to provide a pharmaceutical composition which is characterized by a multi-layered tablet comprising levodoprojin as an active ingredient and a sustained-release tablet, wherein twice a day that 60 mg of levodopropegin has been administered three times a day In addition, the most important characteristic of the administration is the rapid early effective therapeutic blood concentration, and the continuous effective therapeutic blood concentration is maintained, thereby increasing the therapeutic effect. Simplifying the administration of the patient, the convenience of taking the patient and the compliance In a sustained release tablet containing levodoprofen.

In order to accomplish the above object, the present invention provides a sustained-release levodopa stabilizer comprising a slow release layer comprising levodopropegin and a sustained release layer comprising levodoprojin and a release-controlling polymer.

According to the present invention, the two-layered levodopropegin sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained- And as a result, it is very useful because it improves drug adaptability to patients and improves adherence to medication.

Accordingly, the levodoprojine sustained-release tablet according to the present invention has an advantage in terms of the patient's dose and therapeutic effect by solving the problems of levodoprojipine three times daily.

Fig. 1 shows the dissolution test results of the present levodoprofen immediate-release preparation of the present invention.
Fig. 2 shows the dissolution test results of the levodoprojin sustained-release preparation of the present invention.
Fig. 3 shows the dissolution test results of levodoprojin sustained release of the present invention.
Figures 4 and 5 show the results of comparative dissolution tests of the levodoprojine sustained release of the present invention and the control preparation.
6 is a Jung "draw pidgin ^'of the control drug in beagle dogs, compared to <Example 3> Blood repeated oral Lebo draw Pro Pidgin concentration after administration of the formulation, UI04LDP090CT" of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a levodoprofen sustained release tablet comprising a slow release layer comprising levodopropegin and a sustained release layer comprising levodoprojin and release control polymers.

According to a preferred embodiment of the present invention, the content of levodopropegin in the immediate-release layer is 10 to 70 mg, and the content of levodoprojin in the sustained-release layer is 20 to 80 mg. More preferably, the content of levodoprodzine in the immediate-release layer is 30 to 60 mg, the content of levodoprojin in the sustained-release layer is 30 to 60 mg,

The sustained release layer of levodoprojin sustained release of the present invention includes a polymer for emission control. The release-controlling polymer may be any polymer that is pharmaceutically acceptable. Examples of the polymer include hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose (hydroxypropyl cellulose), hydroxypropyl cellulose propylcellulose, sodium carboxymethylcellulose, propylene oxide and derivatives thereof, polyvinylpyrrolidone (molecular weight 90, trade name Povidone K-90), polyethylene glycol (polyethylene glycol) glycol, polyvinyl alcohols, polyvinylacetate, polyvinylacetate phthalate, polymethacrylate, polymer of polymethacrylate (commercially available as Eudragit), polyacrylic acid (Polyacrylic acid), polymetal Derivatives of the rate (typically a carbomer), glycerol monostearate and Pollock four meoro may be one or two or more selected from the group consisting of a mixture. Preferably, a mixture of one or more selected from the group consisting of hydroxypropylmethylcellulose, carbomer, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and polyvinyl alcohol can be used.

According to a preferred embodiment of the present invention, the content of the release-controlling polymer contained in the sustained-release levodoprojin is 10 to 80% by weight based on the total weight of the sustained-release levodoprofen. More preferably, the content of the polymer for emission control is 10 to 60% by weight.

According to another preferred embodiment of the present invention, the viscosity of the polymer for emission control is preferably 60,000 to 140,000 cps.

Of these, hydroxypropylmethylcellulose is known to have various viscosity products, and the dissolution rate of levodoprodipine can be controlled by controlling the viscosity of hydroxypropylmethylcellulose.

The hydroxypropylmethylcellulose contained in levodoprojin sustained-release tablet according to the present invention may be hydroxypropylmethylcellulose having a high viscosity. When the viscosity is 60,000 cps to 140,000 cps and the viscosity is less than 60,000 cps, a large amount of hydroxypropylmethylcellulose The size of the tablet is increased because methyl cellulose is required. When the viscosity exceeds 140,000 cps, uniform mixing with the drug becomes difficult.

The immediate-release layer and the sustained-release layer of the levodoprojin sustained-release composition of the present invention may further contain excipients of various components used in pharmaceutical compositions in the art besides the levodopro- pine and the release-controlling polymer, respectively. For example, one or more excipients selected from the group consisting of disintegrants, lubricants, water-soluble additives, fast-acting excipients, fillers and binders, which are commonly used in the manufacture of pharmaceutical compositions.

The disintegrant is used to absorb water and promote disintegration of the preparation to improve the elution of levodoprojin. Examples thereof include croscamellose sodium, sodium starch glycolate, Pregelatinized Starch (Starch 1500 or Prejel), microcrystalline cellulose, crospovidone (cross-linked povidone), polyvinylpyrrolidone (PVP, Povidone), low-substituted Hydroxypropylcellulose (low substituted), alginic acid, carboxymethylcellulose calcium salt and sodium salt, colloidal silica collidal silica, guar gum, magnesium aluminum silicate (Magnesium alumimum silicate), methylcellulose, powdered cellulose, starch and sodium alum Carbonate can be given alone or in mixture of two kinds selected from the group consisting of (sodium alginate).

Preferably, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone and polyvinylpyrrolidone are used as said disintegrant. More preferably, as the disintegrant, crospovidone, sodium starch glycolate or microcrystalline cellulose can be used, and it is most effective when two or more disintegrants are mixed and used. The disintegrant can be added additionally in a pharmaceutically acceptable manner in addition to the solid preparation for oral use, and a secondary disintegrant can be further used for the purpose of more rapid release of the preparation.

The disintegrant may be contained in an amount of 10 to 60% by weight based on the total weight of the immediate-release layer or the sustained-release layer.

In order to improve the moldability of levodoprojin sustained-release tablets of the present invention, a lubricant is used. Examples thereof include magnesium stearate, silica (SiO ₂ ), collidal silica (Cabo -SIL), talc, and the like, but are not limited thereto. The content of the lubricant is preferably 0.25 to 2% by weight based on the total weight of the immediate layer or the western layer.

The levodoprojin sustained-release tablet of the present invention may further comprise a water-soluble additive generally used in pharmaceuticals. Examples of such additives include lactose, sugar, mannitol, lactose, sorbitol and the like.

The water-soluble additive may be contained in an amount of 10 to 60% by weight based on the total weight of the immediate-release layer or the sustained-release layer.

The levodoprofen sustained-release tablet of the present invention may further contain preservatives, stabilizers and the like, if necessary.

The levodoprojin sustained-release tablet of the present invention is characterized by being pellet-shaped tablets or multiple tablets prepared by mixing the immediate-release layer and the sustained-release layer.

The present invention also provides a process for producing a sustained release granule, comprising: a) mixing levodopropegin, a release controlling polymer and an additive to produce a sustained release granule by wet or dry process; And

b) mixing the lubricant with a mixture containing the sustained-release granule and levodopropegin, respectively, followed by tableting, and then tableting the levodopropegin sustained release tablet.

In the step of preparing a wet sustained release granule, a solvent is added to a mixed powder of levodopropegin, a release controlling polymer and an additive, wherein the solvent includes water, ethanol, isopropyl alcohol, glycerin, propylene glycol and polyethylene glycol May be used. However, water is preferred.

In the step b), a complex tablet machine, a multi-layer tablet machine or a double tablet machine may be used.

As a representative example of the present invention, when preparing the levodoprofen double-layered tablet comprising the immediate layer and the sustained-release layer, the sustained-release layer is firstly pressed and then the inner layer is filled with the inner layer, Can be manufactured. At this time, it is not always necessary to tablet the immediate layer after tableting the slow layer, but tableting of the immediate layer is preferentially performed, and tableting can be performed by filling the granules of the slow layer. Further, it is also possible to fill the inner layer and the middle layer sequentially or in reverse order, and to fix them once.

The levodoprojin sustained-release tablet of the present invention can also be prepared as a single-layer tablets having simultaneous rapid release and sustained release, comprising a two-layer tablet composed of a immediate layer and a sustained-release layer, and a mixed composition of a immediate- And may be manufactured as multiple tablets containing a sustained-release core in the form of a sustained-release layer and a core surrounded by a continuous layer.

Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to the examples.

&Lt; Examples >

1. Basis for setting the amount of raw materials

Check 1) interaction Lebo draw Pro Pidgin and excipients (interaction) and conformance (compatibility)

<Test Method>

90 mg of levodoprofen was mixed with excipients as shown in Table 1, and the initial contents were confirmed. Then, the interaction and compatibility between levodoprope and excipient were evaluated through an accelerated test (temperature 45 ° C, humidity 75%, period 1 month) Respectively.

<Standard>

95 to 105%

additive Initial content test (%) Content test after accelerated test (%) standard result Judgment standard result Judgment Microcrystalline cellulose 95 ~ 105 100.5 fitness 95 ~ 105 100.3 fitness Lactose monohydrate 95 ~ 105 100.1 fitness 95 ~ 105 99.8 fitness Hydroxypropylcellulose 95 ~ 105 99.3 fitness 95 ~ 105 99.2 fitness Hydromelose phthalate 95 ~ 105 99.9 fitness 95 ~ 105 99.2 fitness Carboxymethylcellulose sodium 95 ~ 105 99.9 fitness 95 ~ 105 100 fitness Carboxymethylcellulose calcium 95 ~ 105 100.2 fitness 95 ~ 105 99.8 fitness Copovidone 95 ~ 105 99.3 fitness 95 ~ 105 99.3 fitness Aerosil 95 ~ 105 99.5 fitness 95 ~ 105 99.4 fitness Poloxamer 95 ~ 105 99.4 fitness 95 ~ 105 99.4 fitness * PVP K-30 95 ~ 105 99.3 fitness 95 ~ 105 100 fitness * PVP K-90 95 ~ 105 99.8 fitness 95 ~ 105 99.8 fitness * HPMC2208
(100,000 cp) 95 ~ 105 100.3 fitness 95 ~ 105 99.4 fitness * HPMC2910
(4000 cp) 95 ~ 105 99.7 fitness 95 ~ 105 99.3 fitness Crospovidone 95 ~ 105 99.7 fitness 95 ~ 105 99.2 fitness Magnesium stearate 95 ~ 105 99.9 fitness 95 ~ 105 99.3 fitness Croscarmellose sodium 95 ~ 105 99.8 fitness 95 ~ 105 99.7 fitness Sodium starch (pregelatinized) 95 ~ 105 99.4 fitness 95 ~ 105 100 fitness Low substituted hydroxypropylcellulose 95 ~ 105 99.6 fitness 95 ~ 105 99.5 fitness Mannitol 95 ~ 105 99.5 fitness 95 ~ 105 99.6 fitness Sodium starch glycolate 95 ~ 105 100.4 fitness 95 ~ 105 99.8 fitness Sucrose 95 ~ 105 99.5 fitness 95 ~ 105 99.5 fitness Polyvinyl alcohol 95 ~ 105 99.5 fitness 95 ~ 105 100 fitness Hydroxyethylcellulose 95 ~ 105 99.6 fitness 95 ~ 105 100.3 fitness Sodium alginate 95 ~ 105 99.5 fitness 95 ~ 105 99.8 fitness

* PVP: polyvinylpyrrolidone

* HPMC: Hydroxypropylmethylcellulose

2) Immediate layer  Establishment of formulation

<Test Method>

As shown in Table 2 below, levodoprojin and each excipient were mixed and then tested for fluidity, hardness, fatigue strength, disintegration test and dissolution test.

<Standard>

 Marson degree: 40 tablets 100 revolutions 1% or less

 Flowability: Repose angle less than 40 ℃

Hardness: 4 to 5 kg / cm ²

 Disintegration: visual confirmation (disintegration within 5 minutes), number of specimens 6 each

 Elution: 30min-80% or more

Immediate-release formulation Massono
exam Hardness
exam liquidity
exam Disintegration
exam Dissolution
exam Formulation 1a Levodoprofen (45 mg)
Flowlac (50 mg)
Magnesium stearate (1.9 mg) incongruity fitness - - - Formulation 2a Levodoprofen (45 mg)
Flowlac (60 mg)
Magnesium stearate (1.9 mg) incongruity fitness - - - Formulation 3a Levodoprofen (45 mg)
Flowlac (80 mg)
Magnesium stearate (1.9 mg) incongruity fitness - - - Formulation 4a Levodoprofen (45 mg)
D-mannitol (50 mg)
Magnesium stearate (1.9 mg) incongruity fitness - - - Formulation 5a Levodoprofen (45 mg)
D-mannitol (60 mg)
Magnesium stearate (1.9 mg) incongruity fitness - - - Formulation 6a Levodoprofen (45 mg)
D-mannitol (80 mg)
Magnesium stearate (1.9 mg) incongruity fitness - - - Formulation 7a Levodoprofen (45 mg)
Flowlac (67 mg)
Corn starch (20mg)
Magnesium stearate (1.9 mg) fitness fitness incongruity - - Formulation 8a Levodoprofen (45 mg)
Flowlac (67 mg)
Corn starch (40mg)
Magnesium stearate (1.9 mg) fitness fitness incongruity - - Formulation 9a Levodoprofen (45 mg)
Flowlac (67 mg)
Corn starch (60mg)
Magnesium stearate (1.9 mg) fitness fitness incongruity - - Formulation 10a Levodoprofen (45 mg)
Flowlac (67 mg)
* MCC pH102 (20 mg)
Magnesium stearate (1.9 mg) fitness fitness incongruity - - Formulation 11a Levodoprofen (45 mg)
Flowlac (67 mg)
* MCC pH 102 (40 mg)
Magnesium stearate (1.9 mg) fitness fitness incongruity - - Formulation 12a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (60 mg)
Magnesium stearate (1.9 mg) fitness fitness incongruity - - Formulation 13a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (5 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness fitness Formulation 14a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness fitness Formulation 15a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (20mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity Formulation 16a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
CL-PVP (5 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity Formulation 17a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
CL-PVP (10 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity Formulation 18a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
CL-PVP (20 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity Formulation 19a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Croscarmellose sodium (5 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness fitness Formulation 20a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Croscarmellose sodium (10 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity Formulation 21a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Croscarmellose sodium (20 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity Formulation 22a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Starch 1500 (5 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness incongruity incongruity Formulation 23a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Starch 1500 (10 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity Formulation 24a Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Starch 1500 (20 mg)
Magnesium stearate (1.9 mg) fitness fitness fitness fitness incongruity

* MCC: Microcrystalline cellulose

FIG. 1 shows a dissolution rate graph for Formulation 13 (F-13), Formulation 14 (F-14) and Formulation 19 (F-19).

In order to maintain sustained drug elution, it is very important to control the dissolution profile of the slow release. If the dissolution of the fast-dissolving agent rapidly increases, the drug is hardly exhibited sufficient pharmacological activity due to the nature of the preparation having a half-life of 1 hour. Therefore, the most ideal formulation for this test was formulation 14a, which is a relatively low-dose formulation with a dissolution rate of 5 to 15 minutes.

Therefore, in order to increase the fluidity of levodoprofen, flowlac of meggle, microcrystalline cellulose PH102 as a filler, and sticking are used as a filler when preparing the immediate layer of the levodoprojin sustained-release tablet of the present invention Magnesium stearate was used to prevent it, and sodium starch glycolate was used in combination to increase the initial dissolution rate.

3) West floor  Establishment of formulation

<Test Method>

The inner layer mixed as in Formulation 14a and the sustained-release layer prepared by wet granulation of the formulation as shown in Table 3 below were tableted with two-layer tablets and subjected to a fluidity test, a hardness test and a dissolution test, Respectively.

<Standard>

 Flowability: Repose angle less than 40 ℃

Hardness: 4 to 5 kg / cm ²

 Elution: 30min-40-60%, 180min-60-80%, 720min-85% or more

Formulation Hardness test Liquidity test Dissolution
exam Immediate layer West floor Formulation 1b Levodoprofen (45 mg)
Flowlac (67 mg)
* MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
Colidon SR (10 mg)
Magnesium stearate (1.7 mg) fitness incongruity - Formulation 2b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
Colidone SR (30 mg)
Magnesium stearate (1.7 mg) fitness incongruity - Formulation 3b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
Colidon SR (50 mg)
Magnesium stearate (1.7 mg) fitness incongruity - Formulation 4b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
HPMC 2208 (100,000 cps) (10 mg)
Magnesium stearate (1.7 mg) fitness incongruity - Formulation 5b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
HPMC 2208 (100,000 cps) (30 mg)
Magnesium stearate (1.7 mg) fitness incongruity - Formulation 6b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness incongruity - Formulation 7b
Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
Lactose (5 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 8b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
Lactose (10 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 9b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
Lactose (15 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 10b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (5 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 11b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (10 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 12b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (15 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 13b Pro-pidgin (45 mg) on fp board
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-30 (3 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 14b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg)
Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-30 (6 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 15b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-30 (9 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 16b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-30 (9 mg)
HPMC 2208 (100,000 cps) (60 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 17b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-30 (9 mg)
HPMC 2208 (100,000 cps) (80 mg)
Magnesium stearate (1.7 mg) fitness fitness fitness Formulation 18b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-30 (9 mg)
HPMC 2208 (100,000 cps) (100 mg)
Magnesium stearate (1.7 mg) fitness fitness fitness Formulation 19b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-90 (3 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness fitness Formulation 20b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-90 (6 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness fitness Formulation 21b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-90 (9 mg)
HPMC 2208 (100,000 cps) (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 22b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-90 (9 mg)
HPMC 2910 (50 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 23b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-90 (9 mg)
HPMC 2910 (80 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity Formulation 24b Levodoprofen (45 mg)
Flowlac (67 mg)
MCC pH 102 (67 mg)
Sodium starch glycolate (10 mg)
Magnesium stearate (1.9 mg) Levodoprofen
(45 mg)
MCC pH 101 (7 mg)
PVP K-90 (9 mg)
HPMC 2910 (100 mg)
Magnesium stearate (1.7 mg) fitness fitness incongruity

* MCC: Microcrystalline cellulose

F-14 (genus) / F-19 (genus) / F-18 (F-14) (F-14) and F-20 (F-14) are shown in FIG.

It is important that the initial dissolution rate appears quickly to a certain point and that the effective blood concentration of the drug is constantly maintained until 12 hours. As a result of the test, formulation 19b is the slowest release agent that is the easiest to dissolve and maintains a relatively constant concentration .

4) Establish final formulation

<Test Method>

As a result of the above test, it was confirmed that Formulation 14a was the immediate-release layer and Formulation 19b was the Formulation 19b. In the case of Formulation 19b, the final formulation was prepared so as to have an excipient content close to the upper and lower limits of the elution standard, Respectively.

 Final formulation Example 1 Example 2 Example 3 West floor Levodoprofen 45.0 45.0 45.0 * MCC 101 7.0 6.8 6.8 * HPMC 2208 50.0 50.0 50.0 * PVP K-90 3.0 2.7 2.7 * s-Mg 1.7 1.7 1.7 Final weight (mg) 106.7 106.2 106.2 Immediate layer Levodoprofen 45.0 45.0 45.0 Flowlac 67.0 67.0 67.0 MCC pH102 67.0 67.0 67.0 Sodium starch glycolate 10.0 10.0 7.5 s-Mg 1.9 1.9 1.9 Final weight (mg) 190.9 190.9 188.4 Total Weight (mg) 297.6 297.1 294.6

* MCC: Microcrystalline cellulose

* HPMC: Hydroxypropylmethylcellulose

* PVP K-90: Polyvinyl pyrrolidone K-90

* s-Mg: magnesium stearate

As shown in FIG. 3, the formulation most suitable for the dissolution test was found to be the formulation of < Example 3 > in Table 4.

2. Nonclinical studies: In the case of biggle dogs Pharmacokinetic evaluation after single oral administration

As a control, drospigin tablets of Kolon Pharmaceutical Co., Ltd. were used as a test preparation, and Example 3> UI04LDP090CT of Korea United Pharmaceutical Co., Ltd. was used as a test preparation. In a beagle dog, 3 tablets of the control preparation and 2 tablets of the test preparation were repeatedly orally . The concentration of levodoprojipine in the blood according to the time obtained after oral administration is shown in Fig.

The AUC _{t values} were 5318.39 and 5722.13 hr * ng / mL, the Cmax values were 1205.72 and 1295.53 ng / mL, the Tmax values were 1.08 and 0.83 hr, respectively, and the t1 / 2 Were 2.43 and 1.89 hr, respectively.

When the ratio of the test substance-administered group to the control substance administration group was calculated from the above value, AUC _t 92.9%, and Cmax was 93.1%. It was found that the dose change according to the difference of the contents of the test substance and the control substance did not show a large difference in AUC _t and Cmax. The blood concentration of the initial drug due to the characteristics of the preparation was higher than that of the test substance administration group in the control substance administration group up to 1.5 hours after the administration, but thereafter, the test substance administration group maintained a higher level than the control substance administration group. Therefore, it can be confirmed that the test preparation which is a sustained-release preparation shows a sustained effect even in vivo.

3. With a commercial formulation  compare

Tabulated specimen The elution test of <Example 3> formulation and commercially available levodopropegin 60 mg in Table 4 was performed to compare the dissolution profiles of levodoprodine sustained release tablets. As shown in FIG. 4 and FIG. 5, in the case of commercially available levodopropegin 60 mg, levodoprojin 60 mg was eluted within 30 minutes, while in the case of the preparation of Example 3, 60 mg eluted within 1 hour, The dissolution rate was increased and the dissolution rate was gradually increased until 12 hours, so that the release rate of 90 mg of the drug was kept constant.

<Example 3> After oral administration of the preparation, a rapid effective therapeutic blood concentration was reached at an early stage and the sustained effective therapeutic blood concentration was maintained. Thus, the conventional administration of levodoprojin 60 mg three times a day was twice It is possible to improve the convenience of taking the patient and the compliance with taking.

In-vivo tests on beagle dogs showed that there was a difference in efficacy according to the difference in the initial release of the drug when compared with the in-vitro results of commercially available levodopropegin 60 mg. The difference of Tmax between 60 mg of propidine and the test drug was within 15 minutes, and when Cmax was calculated as a ratio, it was found that there was not a large difference by more than 90%.

This is because the levodoprojine drug itself has a short half-life and does not show a difference in Tmax. Therefore, the levodoprojine sustained-release tablet of the present invention has a sustained-release property, and in-vitro levodoprofen 60 mg , It is expected that Cmax and Tmax will be the same as that of commercially available levodoprofen 60 mg in the in vivo even if the initial reaction time is delayed about 60 minutes. Therefore, when administered to humans, the same effect and efficacy as the commercially available levodoprojipin 60 mg You can expect.

Claims (1)

A levodoprodzine sustained-release layer tablet comprising a slow-release layer containing levodoprojin and a sustained-release layer comprising levodoprojin and a release-controlling polymer,
The sustained release layer contained 45.0 mg levodopropegin, 6.8 mg microcrystalline cellulose (MCC), 50.0 mg hydroxypropylmethylcellulose (HPMC) having a viscosity of 100,000 cps, 2.7 mg polyvinylpyrrolidone (PVP) And 1.7 mg of magnesium stearate (s-Mg)
The immediate-release layer contained 45.0 mg of levodopropegin, 67.0 mg of lactose, 67.0 mg of microcrystalline cellulose (MCC), 7.5 mg of sodium starch glycolate and 1.9 mg of magnesium stearate (s-Mg &Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;

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