KR20020096440A - Controlled release formulation containing Apomophine for oral - Google Patents

Abstract

PURPOSE: A process of preparing an apomorphine formulation for oral use by granulation of apomorphine, spraying a coating liquid at low temperature and spraying the coating liquid at high speed while floating the coating liquid at low temperature is provided. Whereby, the formulation is excellent in treatment of erectile dysfunction. CONSTITUTION: An excipient, binder and solvent are added to a mixed powder containing 1 to 10% by weight of apomorphine or acid salts thereof, 20 to 40% by weight of ascorbic acid, 10 to 20% by weight of domperidone to produce apomorphine granules. A coating liquid comprising 1 to 30% by weight of a coating base, 0.1 to 1.0% by weight of a plasticizer and a solvent is coated on 30 to 40% by weight of the granules at 30 to 40deg.C to produce first coated granules. A coating liquid comprising 1 to 30% by weight of a coating base and 0.1 to 1.0% by weight of a plasticizer is coated on 30 to 40% by weight of the first coated granules at 30 to 40deg.C to produce second coated granules. Thereafter, 40 to 50% by weight of apomorphine, 20 to 30% by weight of the first coated granules and 30% by weight of the second coated granules are mixed.

Description

Controlled release formulation containing Apomophine for oral

The present invention relates to apomorphine controlled release oral preparations containing apomorphine or acid addition salts thereof and having reduced side effects, and methods for preparing the same.

Apomorphine is usually administered in the form of sublingual tablets to patients with psychogenic erectile dysfunction, which is known to be effective approximately 15 to 20 minutes before sexual activity. Although apomorphine is actually known to induce erection in these male patients, it is known that apomorphine dosing, which can cause an erection reaction, has side effects such as nausea, headache, high blood pressure, and sweating.

In the present invention, such side effects are defined as a phenomenon due to the rapid bioabsorption of apomorphine, and a controlled release oral dosage form that can control the absorption of apomorphine has been developed. In the present invention, the oral dosage agent granulates apomorphine with a stabilizer, an anti-emetic agent, and coats it stepwise to control drug release time, thereby preventing side effects due to rapid absorption of the drug and maintaining the drug concentration for a relatively longer time than the existing sublingual setting. It relates to a controlled release oral capsule formulation that can be.

Male erectile dysfunction is defined as a disease in which erections do not last long enough to have a physical relationship, and the causes are thought to be psychological, physiological and neurological factors, and a combination of these factors.

The number of erectile divers is estimated at 30 million in the United States alone, and the number tends to increase dramatically due to aging society, stress and various environmental causes. Treatments for erectile dysfunction include penile transplantation and intra- penis injection of alprostadil, and in 1998, sildenafil was first approved as an oral drug for treating erectile dysfunction in men. It has reverberated.

Recently, ointments that have an effect on erectile dysfunction containing vasodilators such as papaverine, hydralazine, nitroprusside, phenoxybenzamine or phentolamine have been introduced. (See US Pat. No. 4,801,587, Jean Boss et al.).

Apomorphine is a dopamine receptor agonist used in the treatment of Parkinson's disease and is known to have effects on male erectile dysfunction of psychogenic factors. However, the amount of apomorphine required to actually cause an erection reaction is known to be accompanied by side effects such as nausea, hypertension, dizziness, hot flashes, as described above. In order to prevent such side effects, a combination prescription such as antihistamines or anti-emetic drugs has been proposed, which is actually known to reduce side effects.

Apomorphine is mainly administered in the form of sublingual tablets, which has a bioavailability of about 13% compared to subcutaneous injection. Thus, it is administered in the form of sublingual tablets at a dose of about 2 to 8 mg, which has a bioavailability of about four times that of oral preparations (see US Pat. No. 5,994,363, Ragab el-Lassidi et al.). Apomorphine sublingual tablets, however, generally exhibit Tmax at 15 minutes after administration and exhibit these side effects due to such rapid in vivo absorption, which is a major cause of avoiding drug selection (US Pat. No. 6,121,276, Ragab El- See Rashidi et al.).

It is an object of the present invention to provide an apomorphine oral dosage form and a method for preparing the apomorphine, which express only drug efficacy without side effects upon oral administration. The preparation of the present invention expresses side effects due to the rapid sublingual absorption of the existing sublingual tablets, and it is much easier to take compared to the short action time, and significantly reduces the side effects due to release control, and to maintain the action expression time for a long time.

In the present invention is based on the invention of the coated apomorphine granules in which the disintegration time is controlled by granulating apomorphine and coating it using various coating agents.

The coating base is obtained from a variety of polymers and natural extracts of the raw material, and by appropriately mixing and controlling the amount of coating to produce a coating granule different in the release time of the drug. Next, the capsules are mixed with uncoated drug granules, coated granules with a 10-minute delay in release time, and coated granules with a 30-minute delay in drug release, which is simpler than the existing sublingual setting, and also rapidly absorbs apomorphine. It prevents the onset of side effects by preventing the drug, and the effect of drug expression is relatively long lasting effect.

1 is apomorphine granules ( ), Primary coating granules (△) and secondary coating granules ( Comparative graph of apomorphine elution test in serous)

Figure 2 is a capsule A of the present invention in a beagle dog Sample A ( ), Sample B ( ), Sample C (△) and sample D (◇) apomorphine blood concentration comparison graph,

Figure 3 is a known sublingual tablet of beagle dogs ( ) And the capsule of the present invention ( Comparative graph of blood concentration of apomorphine after administration,

4 is a placebo ( ), Sublingual ) And the penis columnar comparative graph of the present invention capsule (△),

5 is a placebo ( ), Sublingual ) And penile hardness comparison graph of the capsule (Δ) of the present invention.

Apomorphine-release-controlled oral formulation for treating erectile dysfunction of the present invention has the following configuration.

1) apomorphine granules consisting of 1-10% by weight of apomorphine or acid addition salt, 20-40% by weight of ascorbic acid as a stabilizer, 10-20% by weight of domeperidone as an antiseptic agent, and other excipients, binders and solvents;

2) 1 to 30% by weight of the apomorphine granules of 1), 1 to 30% by weight of the coating base, 0.1 to 1.0% by weight of the plasticizer, and apomorphine primary coated granules coated with a solvent;

3) 30% to 40% by weight of the primary coating granules of 2) are composed of apomorphine secondary coating granules coated with a coating liquid consisting of 1 to 30% of the coating base, 0.1 to 1.0% of the plasticizer, and a solvent.

4) Apomorphine controlled release oral formulation for erectile dysfunction containing 40-50% by weight of apomorphine granules, 20-30% by weight of apomorphine primary coated granules and 30% by weight of apomorphine secondary coated granules. .

In addition, the method for producing a composition of the present invention is composed of the following fixing.

1) Apomorphine granules were prepared by adding 1 to 10% by weight of apomorphine or its acid addition salt, 20 to 40% by weight of ascorbic acid as a stabilizing agent, and 10 to 20% by weight of domeperidone as a stabilizer, by adding an excipient, a binder and a solvent. after,

2) Apomorphine primary coating granules were prepared by coating at 30 to 40 ° C. with a coating liquid consisting of 1 to 30% by weight of a coating agent, 0.1 to 1.0% by weight of a plasticizer and a solvent in 30 to 40% by weight of the apomorphine granules of 1). and,

3) 2) apomorphine secondary coating by coating at 30-40 ° C. with the coating liquid consisting of 1-30% by weight of coating base, 0.1-1.0% by weight of plasticizer and solvent in 30-40% by weight of apomorphine primary coating granule of 2). After preparing the granules,

4) Apomorphine release controlled type for erectile dysfunction treatment, characterized by mixing and homogenizing 40-50% by weight of apomorphine granules, 20-30% by weight of apomorphine primary coated granules and 30% by weight of apomorphine secondary coated granules. It is a manufacturing method of oral preparation composition.

In detail, the method for preparing the composition of the present invention, first, apomorphine is granulated together with a stabilizer, an anti-emetic agent, and the like, and the sprayed coating solution is first sprayed at high speed while the apomorphine granules are suspended at a low temperature, thereby forming a coated granule. Preparation of controlled release apomorphine capsules characterized by mixing the obtained apomorphine granules, primary and secondary coating granules after obtaining a double coated granules by secondary spraying the coating liquid at high speed while floating under low temperature It is a way.

According to the present invention, first, a mixture of 1 to 10% by weight of apomorphine or apomorphine hydrochloride, 20 to 40% by weight of ascorbic acid, and 10 to 20% by weight of domperidone are mixed, and then 30 to 60% by weight of an excipient and a binder. Is added to prepare granules. Granules have a dry method and a wet method, but here, a wet method using water, alcohol, acetone, or the like alone or in combination is used. Excipients and binders include hydroxypropylmethylcellulose, starch, low-substituted hydroxypropylcellulose, carrageenan, pectin, guar gum, xanthan gum, gellan gum, gum arabic, methylcellulose, ethylcellulose, soy protein and soy protein. Alternatively, the artificially processed analogous material, chitin or chitin acid, sodium alginate, heavy carbon fatty acids having 6 to 12 carbon atoms, etc. may be used alone or in combination of two or more thereof.

In the present invention, the coating bases used in the primary and secondary coating of apomorphine granules are corn protein extracts and artificially processed analogous substances, sodium alginate, alginic acid, Eudragit ^о (polymethacrylic acid, polymethacrylate), shellac (shellac ^ⓡ) acids, Carbopol (Carbopol ^ⓡ) acids (Carbomer ^ⓡ, carboxyvinyl polymer), hydroxypropyl methyl cellulose phthalates, hydroxypropyl methyl cellulose acetate succinate, carboxy methyl cellulose , Cellulose acetate phthalates, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, soy protein or small soy protein or artificially processed analogues, chitin, chitin acid or artificially processed analogs, agar, carrageenan (Carrageenan ), Pectin, Guar gum, Locust bean gum, Xanthan gum, Zelan Gel gum, Arabic gum, C6-12 heavy chain fatty acids, etc. may be used alone or in combination of two or more thereof.

The amount of base used for preparing the coating liquid is 1 to 60% by weight based on apomorphine granules, preferably 1 to 30% by weight.

The plasticizer in the coating is polyethylene glycol, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol, glycerin, dibutyl phthalate, triethyl citrate, triethyl citrate, triacetin, cetyl alcohol, stearyl alcohol, etc. It can be used alone or in a mixture of two or more, the amount of plasticizer is 0.1 to 5.0% by weight, preferably 0.1 to 1.0% by weight based on the amount of apomorphine.

If the coating base and the plasticizer are out of the used range, disintegration of the coating granules is delayed, so that rapid drug expression cannot be expected.

Solvents used in the coating include water, ethyl alcohol, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, ethyl acetate, methyl acetate or these It contains a mixture of.

The apparatus used for coating is a so-called "Fluid bed coater", or a similar apparatus in the present invention used a fluidized bed granulator SFC-MINI (Freund Co., Japan), but similar apparatus for the formulation Manufacturing is possible.

As a condition when coating apomorphine granules in a fluidized bed granulator, the temperature of the inlet air is in the range of 40 ° C to 70 ° C, and the air volume of the inlet air is preferably 10 to 30m ³ / min. In addition, the exhaust air volume is appropriately 5 to ¹⁰ m ³ / min. The rotation speed of the rotor is preferably 100 to 500 rpm, the stirring speed of the coating base is 200 to 800 rpm, the rotation speed of the lump breaker is 1500 rpm or more, the speed of the spray liquid is 7 to 25 ml / min, and the air volume of the injection air is 10 to 50 m. ³ / min is suitable, and it is preferable to maintain the temperature of the granules in the coating at 30 to 40 ° C. in order to prevent aggregation of the granules.

Apomorphine-coated granules prepared by the above method should pass through No. 12 to No. 14 and do not pass No. 200, and are verified by measuring the disintegration time of these granules.

Apomorphine granules to be filled in oral capsules are mixed in three proportions, approximately 40-50% by weight of apomorphine granules, 20-30% by weight of apomorphine primary coated granules and 30% of apomorphine secondary coated granules 30 Mix in proportions by weight. A more preferable ratio is 40:30:30 weight%. Through drug dissolution test (see Experimental Example 1), uncoated apomorphine granules and acomorphine primary coated granules with delayed drug release for 10-15 minutes compared to apomorphine granules by coating with the coating agent, and primary coated granules Coated with the coating base to confirm apomorphine secondary coating granules with a drug release time delayed by about 25 to 30 minutes, and these were mixed by a predetermined ratio as described above to make capsules. Because of this, compared to the existing sublingual tablets, Cmax has the characteristic that it is maintained for an unusually long time as an oral drug (see Experimental Example 2).

The present invention has proved its effectiveness in clinical trials with erectile dysfunction (Experimental Example 3). The controlled release of apomorphine-coated granule capsule in Experimental Example 3 shows a long-lasting advantage compared to sublingual setting in circumferential increase and hardness of the penis. In addition, the effect of immediately watching the sexual intercourse video showed that the circumference of the penis and the hardness increased almost the same as the sublingual tablet, indicating that the drug efficacy was not lagging behind, and that it prevented the rapid absorption of the drug as intended. Reduced side effects.

Although the coating method and coating manufacturing process of the apomorphine granules according to the present invention are described in detail with reference to the following examples, it is only described for the purpose of illustrating the present invention, and the claims of the present invention are to be limited to these examples no.

Example 1

Preparation of Apomorphine Granules

Table 1

Apomorphine Hydrochloride 7.7 wt% Ascorbic acid 30.8 wt% Domperidone 15.4 wt% Microcrystalline cellulose 12.3 wt% Low Substituted Hydroxypropyl Cellulose 3.1 wt% Hydroxypropyl cellulose 3.1 wt% water 3.1 wt% Ethyl alcohol 24.5 wt%

Mix the components according to the prescription of Table 1 and assemble them to a size enough to pass through No. 18 to No. 20 sieve. The granules passed are dried in an electric oven at 30 to 50 ° C. for 3 to 5 hours and used as granules, which are then used as a seed for the subsequent coating operation.

Example 2

Preparation of Apomorphine Granules

Table 2

Apomorphine Hydrochloride 7.5 wt% Ascorbic acid 30.5 wt% Domperidone 15.0 wt% Mannitol 20.0 wt% Hydroxypropyl cellulose 4.5 wt% water 3.0 wt% Ethyl alcohol 19.5 wt%

Mixing the ingredients according to the Table 2 prescription to make granules as in Example 1 and write them as Seed of the coating operation to be carried out afterwards.

Example 3

Coating of Apomorphine Granules

Table 3

Primary Coating Seed Apomorphine Granules 500 g Coating base Hydroxypropyl Methyl Cellulose 50 g Plasticizer PEG 6000 5 g Pigment Blue 1 0.5g Coating solution water 200 ml Ethyl alcohol 800 ml 2nd Coating Seed Primary Coated Apomorphine Granules 500 g Coating base Hydroxypropyl Methyl Cellulose 50 g Plasticizer PEG 6000 5 g Pigment Yellow No. 1 0.5g Coating solution water 200 ml Ethyl alcohol 800 ml

The apomorphine granules prepared in Example 1 are coated while spraying the coating solution of Table 3 while floating in a fluidized bed granulator. The spray liquid velocity of the fluidized bed granulator is 10 to 20 ml / min, the air volume of the sprayed air is 30 to 40 m ³ / min, and the temperature in the fluidized bed granulator is not within the range of 30 to 40 ° C.

Example 4

Coating of Apomorphine Granules

Table 4

Primary Coating Seed Apomorphine Granules 500 g Coating base Hydroxypropyl Methyl Cellulose 40 g Plasticizer glycerin 4 g Pigment Blue 1 0.5g Coating solution water 200 ml Ethyl alcohol 800 ml 2nd Coating Seed Primary Coated Apomorphine Granules 500 g Coating base Ethyl cellulose 30 g Plasticizer Diethylphthalate 3 g Pigment Yellow No. 1 0.5g Coating solution Ethyl alcohol 1000 ml

The apomorphine granules prepared in Example 2 are coated while spraying the coating liquid of the above (Table 4) while floating in a fluidized bed granulator. Coating is carried out in the same manner as in Example 3.

Example 5

Coating of Apomorphine Granules

Table 5

Primary Coating Seed Apomorphine Granules 500 g Coating base Methyl Cellulose 20 g Plasticizer Triethyl citrate 3 g Pigment Blue 1 0.4g Coating solution Ethyl alcohol 900 ml 2nd Coating Seed Primary Coated Apomorphine Granules 500 g Coating base Hydroxypropyl Methyl Cellulose 60 g Plasticizer PEG 6000 5 g Pigment Yellow No. 1 0.5g Coating solution water 200 ml Ethyl alcohol 800 ml

The apomorphine granules prepared in Example 1 are coated while spraying the coating solution of Table 5 while floating in a fluidized bed granulator. Coating is carried out in the same manner as in Example 3.

(Example 6)

Coating of Apomorphine Granules

Table 6

Primary Coating Seed Apomorphine Granules 500 g Coating base Hydroxypropyl Methyl Cellulose 50 g Plasticizer PEG 6000 5 g Pigment Blue 1 0.5g Coating solution water 200 ml Ethyl alcohol 800 ml 2nd Coating Seed Primary Coated Apomorphine Granules 500 g Coating base Carboxymethyl Cellulose 40 g Plasticizer PEG 6000 5 g Pigment Yellow No. 1 0.5g Coating solution water 500 ml Ethyl alcohol 500 ml

Apomorphine granules prepared in Example 1 were coated while spraying the coating solution of Table 6 while floating in a fluidized bed granulator. Coating is carried out in the same manner as in Example 3.

(Example 7)

A capsules were prepared by mixing the apomorphine granules prepared in Examples 1 and 3, the first coated apomorphine primary coated granules, and the second coated apomorphine secondary coated granules according to the ratio of the following Table 7.

Table 7

Ratio of apomorphine granules and apomorphine primary and secondary coating granules in capsules

(Unit: weight%)

Apomorphine Granules Primary coated apomorphine coated granules (primary) Apomorphine-coated granules coated up to 2nd (2nd) Sample A 33.4% 33.3% 33.3% Sample B 40.0% 30.0% 30.0% Sample C 50.0% 20.0% 30.0% Sample D 50.0% 40.0% 10.0%

Experimental Example 1

Apomorphine Dissolution Comparison Test in Granular Serum.

Apomorphine granules obtained in Examples 1 and 3, apomorphine primary coated granules and apomorphine secondary coated granules were each tested for drug dissolution in intestinal fluids based on pharmacopoeial test criteria, and the results are shown in FIG. 1. .

As shown in Figure 1 in the drug dissolution experiment, uncoated apomorphine granules ( ) And primary coated apomorphine primary coated granules (△), and apomorphine secondary coated granules first coated and then secondary coated ( ), The drug release was different by 10-20 minutes. Capsules were prepared on the basis of this to prepare oral drugs in which drug release continued at a constant concentration for a period of time.

Experimental Example 2

Capsule blood concentration comparison test.

In Example 1, four capsules were prepared according to Table 7 of Example 7 with the apomorphine granules that had undergone the dissolution test.

Four capsules were prepared by mixing apomorphine granules, primary coated apomorphine primary coated granules, and secondary coated apomorphine secondary coated granules according to the apomorphine weight based on the table, and the total amount was based on apomorphine. To 2 mg. After oral administration to 10Kg of beagle dogs, blood concentration of apomorphine was measured and shown in FIG. 2.

In the above results, sample D tends to reach Cmax too quickly and sample A tends to reach effective blood concentration too late. Sample B and sample C may be appropriate, but sample B, which stays in the effective blood concentration for a relatively long time, is considered to be appropriate. According to the experimental results, various types of blood concentration curves can be obtained according to the prescription ratio of coated apomorphine granules. In practice, each prescription ratio can be determined according to the individual for clinical application. I think it is possible to make a prescription.

Experimental Example 3

Comparison of blood levels of sublingual tablets and capsules of the present invention.

Blood concentrations in beagle dogs with the apomorphine-coated granules prepared in the above examples were compared with existing known sublingual tablets. Sublingual tablet US Pat. Sublingual tablet of Table IV of No.6,121,276 (5.0 mg of apomorphine hydrochloride, 5.0 mg of ascorbic acid, 58.9 mg of mannitol, 1.0 mg of stearate, 10.0 mg of domperidone, 20.0 mg of betacyclotextine, D & C Yellow 10 Aluminum Lake 0.1 mg, total 100 mg) was prepared and used in the experiment at a concentration of 0.2 mg / kg, the controlled release oral capsule formulation of the present invention (Example 7 Sample B) to prepare apomorphine granules according to Example 1 Then, the coating was carried out according to Example 3, and then the apomorphine-coated granules prepared in Example 1, the acomorphine-coated granules coated first, and the apomorphine-coated granules coated up to the second were 40:30:30, respectively. Mix it so that the total amount of apomorphine in the capsule is 0.2 mg / kg equal to the sublingual tablet. After administration to beagle dogs, blood concentrations of each apomorphine were measured and shown in FIG. 3.

In the above results, the capsule preparation of the present invention mixed with the coated granules showed a moderate increase in blood concentration compared to the existing sublingual tablets, and also appeared to stay at the effective drug concentration for a long time. This is expected to play a role in reducing side effects and increasing the effect time as intended.

Experimental Example 4

Erectile Dysfunction Clinical Trial and Observation of Side Effects.

Clinical trials were performed on erectile dysfunction patients with conventional apomorphine sublingual tablets, placebo and controlled release capsules used in the above experiments. Sublingual tablet US Pat. No. Sublingual tablet of Table IV of Table 6,121,276 (5.0 mg apomorphine hydrochloride, 5.0 mg ascorbic acid, 58.9 mg mannitol, 1.0 mg magnesium stearate, 10.0 mg domeperidone, 20.0 mg betacyclotextine, D & C Yellow 10 Aluminum Lake 0.1 Mg, total 100 mg) was used in the experiment, controlled release oral capsule formulation of the present invention (Example 7 Sample B) Apomorphine granules were prepared according to Example 1 and coated according to Example 3. Next, apomorphine granules prepared in Example 1, acomorphine-coated granules coated first, and apomorphine-coated granules coated up to the second were mixed at a ratio of 40:30:30, respectively, and the total amount of apomorphine in the capsule was 5 mg. This was used for the experiment.

In clinical trials, 15 patients were selected from the ages of 30 to 50 years who were diagnosed with mental dysfunction by urologists. They were divided into three groups of five people, each receiving a placebo, apomorphine sublingual tablet, and a controlled release capsule 10 minutes after 10 minutes of sexual video stimulation. The effects of these drugs were measured by measuring the hardness of the glans of the penis and the increase in the circumference of the penis until 120 minutes after dosing. Measurement of the penile columnar and the hardness of the penis head region recorded their scores according to Table 8 and Table 9 criteria. 11, 20, 40, 60, 80, 100, and 120 minutes after the administration of the drug, and the various side effects appearing after the drug was recorded in detail in each patient to investigate the expression of the side effects. The measurement result of penile columnar is shown in FIG. 4, and the measurement result of penis hardness is shown in FIG. 5, and the results of side effect expression investigation are shown in Table 10.

Table 8

Erectile function measurement table due to increase in penile columnar

Penile columnar increase (cm) Score 0-<0.5 One 0.5-<0.5 2 1.0-<1.5 3 1.5-<2.0 4 2.0-<2.5 5 2.5-<3.0 6

Table 9

Erectile function measurement table according to penis hardness

Penile Hardness (%) Score 0-<10 One 10-<20 2 20-<30 3 30-<40 4 40-<50 5 50-<60 6 60-<70 7 70-<80 8 80-<90 9 90-<100 10

From the above experimental results, it was found that the erectile response of the previously known sublingual tablets and the controlled release capsule of the present invention was successful in both formulations immediately after watching the sexual intercourse video. However, as time passed, the release-controlled capsule of the present invention was observed that the circumferential increase and hardness of the penis last much longer than the known sublingual tablet. In particular, when one hour elapsed after taking apomorphine, the known sublingual tablets mostly lost the results, whereas the controlled release capsule of the present invention was observed to have an erection function lasting up to 120 minutes.

Table 10

Side effects due to placebo, sublingual tablet, controlled release capsule

Experimental group Side Effect Placebo group Patient # 1 Patient # 2 Patient # 3 Patient # 4 Patient # 5 Not Observed Not Observed Not Observed Not Observed Sublingual administration group Patient # 1 Patient # 2 Patient # 3 Patient # 4 Patient # 5 8 minutes after administration nausea, vomiting complaints, dizziness complaints, and facial recalled, lasting up to 48 minutes, starting yawning from 5 minutes after administration, headache complaints, dizziness, recalled facials, not observed until 40 minutes Start yawning from 4 minutes after administration, lasting until 28 minutes Start yawning and facial from 5 minutes after dosing, headache complaint about 12 minutes, last until 58 minutes Controlled Release Capsule Patient # 1 Patient # 2 Patient # 3 Patient # 4 Patient # 5 Not observed Not observed Not observed Start yawning 10 minutes after treatment, Intermittent yawning until around 68 minutes Temporary headache observation, Recall of facial recovery 42 minutes

As can be seen in Table 10, the well-known sublingual tablet administration group was found to have side effects in four out of five, three of the five (60%) considering the minor side effects that can also appear generally Had side effects such as headaches and dizziness. However, in the controlled-release capsule-administered group of the present invention, 3 out of 5 patients did not show any adverse effects, only 1 yawn appeared, and only 1 of 5 (20%) patients had drug side effects when considering only patients with temporary headache. It can be said that this appeared. As a result, the side effects of apomorphine drug expression can be prevented through the gradual absorption of the drug and the controlled release apomorphine capsules through the coating granules according to the present invention can reduce the side effects compared to conventional known agents. It is considered to be a good formulation.

According to the present invention, by preparing the apomorphine granules, the primary coating granules, the secondary coating granules with different drug anti-shrinkage rate and containing them in a constant ratio, oral administration, the absorption rate of the drug is gradually controlled, such as headache or dizziness. It can reduce the side effects of and can provide an apomorphine controlled release oral preparation excellent in the effect of treating erectile dysfunction, the present invention must be very useful industrially.

Claims (9)

Apomorphine release-controlled oral formulation for treating erectile dysfunction having the following configuration. 1) 1 to 10% by weight of apomorphine or acid addition salt thereof, 20 to 40% by weight of ascorbic acid as a stabilizer, 10 to 20% by weight of domperidone as an antiseptic agent, and apomorphine granules composed of other excipients, binders and solvents; 2) apomorphine primary coated granules coated with a coating liquid consisting of 30 to 40% by weight of the apomorphine granules of 1) in a coating liquid consisting of 1 to 30% by weight of a coating base, 0.1 to 1.0% by weight of a plasticizer, and a solvent; 3) 2) 30 to 40% by weight of the primary coating granules is composed of apomorphine secondary coating granules coated with a coating liquid consisting of 1 to 30% by weight of the coating base, 0.1 to 1.0% by weight of the plasticizer and a solvent, 4) Apomorphine controlled release oral formulation for treating erectile dysfunction containing 40-50% by weight of apomorphine granules, 20-30% by weight of apomorphine primary coated granules and 30% by weight of apomorphine secondary coated granules. The composition according to claim 1, wherein the coating base is hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, xanthan gum, gum arabic or a mixture of two or more thereof. The composition of claim 1, wherein the mixing ratio of the apomorphine granules, the apomorphine primary coated granules, and the apomorphine secondary coated granules is 40: 30: 30% by weight. The composition of claim 1, wherein the oral formulation is a capsule. Method for producing apomorphine-release controlled oral formulation composition for treating erectile dysfunction consisting of the following steps. 1) 1 to 10% by weight of apomorphine or its acid addition salt, 20 to 40% by weight of ascorbic acid as a stabilizer, 10 to 20% by weight of domperidone as an antiseptic agent, and excipients, binders and solvents are added to the mixed powder to prepare apomorphine granules. After that, 2) Apomorphine primary coated granules were prepared by coating a coating solution consisting of 1 to 30% by weight of a coating base, 0.1 to 1.0% by weight of a plasticizer and a solvent at 30 to 40 ° C in 30 to 40% by weight of the apomorphine granules of 1). and, 3) Apomorphine secondary coated granules were prepared by coating at 30 to 40 ° C. with a coating liquid consisting of 1 to 30 wt% of the coating base, 0.1 to 1.0 wt% of the plasticizer, and a solvent in 30 to 40 wt% of the primary coating granule of 2). next, 4) Apomorphine release controlled type for erectile dysfunction treatment, characterized by mixing and homogenizing 40 to 50% by weight of apomorphine, 20 to 30% by weight of apomorphine primary coated granules, and 30% by weight of apomorphine secondary coated granules. Method for preparing oral preparation composition. The method according to claim 5, wherein the coating base is hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, xanthan gum, gum arabic or a mixture of two or more thereof. The method according to claim 5, wherein the mixing ratio of the apomorphine granules, apomorphine primary coating granules and apomorphine secondary coating granules is 40: 30: 30% by weight. The method according to any one of claims 5 to 7, wherein the oral preparation is a capsule. The method according to claim 5, wherein the coating operation is performed by maintaining the internal temperature of the fluidized bed granulator at 30 to 40 ℃.