WO2020166835A1 - Method for preparation of levodropropizine-containing, sustained-release tablet - Google Patents

Abstract

The present invention relates to a method for preparation of a levodropropizine-containing, sustained-release tablet composed of a sustained release layer responsible for delayed release, and an immediate release layer, each layer containing levodropropizine. When prepared by the method of the present invention, the levodropropizine-containing, sustained-release tablet is superb in terms of dissolution as well as formulation characteristics such as friability, hardness, preparation uniformity, and so on and thus exhibits excellent stability during long-term storage and transport.

Description

Manufacturing method of sustained-release tablet containing levodropropazine

The present invention relates to a method of manufacturing a sustained-release tablet containing levodropropizine, each containing levodropropizine in a sustained-release layer and an immediate-release layer in which delayed-release is made.

This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0015835 filed on February 12, 2019, and all contents disclosed in the documents of the Korean patent application are incorporated as part of this specification.

Levodropropizine inhibits c-fiber, a peripheral nerve involved in cough reflex, and prevents inflammatory reactions, bronchospasm, airway hyperactivity, mucus hypersecretion, vascular permeability, and cough reflex induced by neuropeptides at the c-fiber end. It has an inhibitory effect.

At least 75% of levotropin is absorbed when administered orally, and the time to reach the maximum blood concentration is about 0.25-1 hour, after that, about 35% of levotropin in the body is excreted, and the excretion rate (half-life) is about 1 It is known to be about time.

Levodropropizine is currently developed and marketed in tablet form, and 60mg is administered once a tablet, three times a day.

In the case of commercially available levotropizine formulations, there is no problem in rapid pharmacological expression due to dissolution and absorption immediately upon administration. 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 conventional agents, and also reduce the side effects. By reducing the frequency of administration, the patient's adherence to medication is improved and 3 times a day. There is a growing need for sustained-release formulations of levodropropizine that can eliminate discomfort caused by ingestion.

Accordingly, Korean Patent Publication No. 10-2011-0113413 (Patent Document 1) discloses a sustained-release pharmaceutical composition comprising levodropropizine as an active ingredient and a method for preparing the same.

For the sustained-release formulation of levodropropizine, the initial dissolution rate is at a certain point in two-layer tablets, double-layer tablets, and multi-layer tablets (formulations consisting of an immediate-release layer and a sustained-release layer), which are formulations that satisfy the initial rapid expression of pharmacological activity and sustained drug efficacy at the same time. It is important to quickly appear up to and maintain the effective blood concentration of the drug consistently for up to 12 hours.

On the other hand, Korean Patent Registration No. 10-1811700 (Patent Document 2) uses a high-viscosity hydroxypropylmethylcellulose to contain a matrix-type sustained-release part containing levodropropizine and a tablet amount of levotropin for rapid initial treatment. It has been found that the above task can be achieved by formulating the immediate release portion together.

In the patent document 2, a multi-layered tablet consisting of an immediate-release layer and a sustained-release layer containing levodropropizine as an active ingredient was prepared, so that the conventionally administered levodropropizine 60mg three times a day can be administered twice a day. In addition, the most important feature when taking the drug is to increase the therapeutic effect by reaching the effective treatment blood concentration at an early stage and maintaining the effective treatment blood concentration continuously, and simplifying the patient's dosing regimen to improve the patient's convenience and compliance. It presents a specific composition for sustained-release tablets containing levodropropazine that can be used.

However, in the case of a multi-layered tablet including a sustained-release tablet composed of an immediate-release layer and a sustained-release layer, physical properties such as friability may be lowered compared to a tablet formulation composed of a single layer, and a peeling phenomenon in which each layer is separated during storage and transport. Can occur. Therefore, in order to improve the stability in the distribution process, such as long-term storage and transport, while enabling mass production, a novel manufacturing technology of levodropropizin sustained-release double-layer tablet is required.

The present invention relates to a method for manufacturing a two-layer tablet comprising an immediate-release layer containing levodropropizine and a sustained-release layer containing levodropropizine and a release-controlled polymer, and has improved stability even in the above-described distribution process. It provides a novel manufacturing method for manufacturing a sustained-release two-layer tablet containing dropropizine.

In order to achieve the above object, the sustained-release double-layer tablet containing levodropropizine according to the present invention may be prepared including the following steps.

Preparing immediate-release granules containing levodropropizine, a disintegrant and a lubricant (s1);

Preparing a sustained-release layer granules containing levodropropizine, a release-controlled polymer, a binder, and a lubricant (s2);

Compressing the sustained-release layer granules and the immediate-release layer granules with a tablet press to have a hardness of 5 to 18/cm 2 (s3).

At this time, if the hardness is less than 5kg/cm2, it may not be possible to manufacture a tablet or the formulation may collapse during storage, and if the hardness exceeds 18kg/cm2, dissolution is delayed and the optimum dissolution profile cannot be achieved.

In order to manufacture a tablet having the above hardness range, it is preferable to perform tableting at a position under the main pressure of 7mm to 12mm. If the position under the main pressure is less than 7 mm, the hardness of the formulation is excessively increased, and drug dissolution is delayed, so rapid pharmacological action cannot be expressed at the initial stage of oral administration. On the other hand, if it exceeds 12 mm, the friability is increased, and thus the storage stability of the formulation is deteriorated, which is not suitable.

In this case, the content of levodropropazine in the immediate-release granules may be preferably 10 to 70 mg, more preferably 30 to 50 mg. In addition, the content of levodropropazine in the sustained-release layer granules may be 20 to 80 mg, more preferably 35 to 60 mg.

Meanwhile, the disintegrating agent of the immediate-release layer granules may be used by selecting one or a mixture of two or more from the group consisting of sodium starch glycolate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, and crospovidone.

In addition, the lubricant may be one or two or more selected from the group consisting of magnesium stearate, light anhydrous silicic acid, talc, and sodium stearyl fumarate.

The sustained-release layer granules may contain a binder, wherein as a binder, one or two selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetate, copovidone, and ethylcellulose The above mixture can be used.

In addition, the sustained-release layer granules may contain a release-controlled polymer for controlling the delayed-release rate of the drug. The release-controlling polymer may be one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, collidone SR, and carbomer.

At this time, the release-controlled polymer may be included in an amount of 30 to 60% by weight based on the total weight of the granules of the sustained-release layer.

The total weight of the sustained-release double-layer tablet containing levodropropizine prepared by tableting the immediate-release layer granules and the sustained-release layer granules may be 250 to 350 mg, and preferably 270 to 320 mg.

The weight of the immediate-release granules and the sustained-release granules among the total weight of the tablet is characterized in that the weight of the immediate-release granules is relatively large, and the weight ratio of the immediate-release granules and the sustained-release granules is 1.5:1 to 2.5:1.

Meanwhile, the turret speed of the tablet press in step s3 is preferably 12 to 28 rpm, more preferably 15 to 25 rpm, and most preferably 21 to 25 rpm.

In the step s3 of tableting the immediate-release layer granules and the sustained-release layer granules to prepare a two-layer tablet, the immediate-release layer granules are first filled in a tablet press and tableted to prepare an immediate-release layer tablet, and then the sustained-release layer granules are additionally filled in the tablet press. It is more preferable because the process is easy when producing a two-layer tablet by tableting.

The sustained-release two-layer tablet containing levodropropizine prepared by the manufacturing method according to the present invention has excellent friability, and is characterized by high stability even when the tablet is stored and moved in a virtue bottle.

1 shows the hardness and dissolution rate for a preferred preparation example of a two-layer tablet prepared by first tableting a sustained-release layer using a double tablet tableting machine and then tableting an immediate-release layer.

Figure 2 shows the hardness and dissolution rate for a preferred preparation example of a two-layer tablet prepared by first tableting the immediate-release layer and then the sustained-release layer using a double tablet tablet press.

Terms used in the present specification and claims are not limited to their usual or dictionary meanings and should not be interpreted, and that the inventor can appropriately define the concept of terms in order to describe his own invention in the best way. Based on the principle, it should be interpreted as a meaning and concept consistent with the technical idea of the invention. Therefore, the configuration of the embodiments described in the present specification is only one of the most preferred embodiments of the present invention and does not represent all of the technical spirit of the present invention, and thus various equivalents and equivalents that can replace them at the time of the present application It should be understood that there may be variations.

The terms "about" and "substantially" used throughout this specification are used as meanings at or close to the numerical values when manufacturing and material tolerances specific to the stated meanings are presented, and are accurate to aid understanding of the present application. Or absolute figures are used to prevent unfair use of the stated disclosure by unconscionable infringers.

The term "main pressure lower position" used throughout the present specification refers to a distance between the tablet press die in which raw materials are injected and the lower punch of the tablet press that serves to apply pressure when the main pressure is applied for tablet tableting. For example, in the case of “compacting tableting at a lower position of the main pressure 5 mm”, it means performing tableting while the separation distance between the die of the tablet press and the lower punch is 5 mm. In the present invention, it is possible to control the hardness of the tablet during tableting by adjusting the lower position of the main pressure.

In the entire specification of the present application, the term "combination(s) thereof" included in the expression of the Makushi form means one or more mixtures or combinations selected from the group consisting of the constituent elements described in the expression of the Makushi form, It means to include at least one selected from the group consisting of the above components.

In the entire specification of the present application, the description of "A and/or B" means "A or B or both".

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

In order to prepare the sustained-release two-layer tablet containing levodropropizine according to the present invention, first, immediate-release granules and sustained-release granules containing levodropropizine are prepared. At this time, the order of preparing the immediate-release layer granules and the sustained-release layer granules may be done first.

The immediate-release layer and the sustained-release layer granules will be described.

The immediate-release layer granules contain levodropropizine, a disintegrant and a lubricant, and the content of levodropropazine in the immediate-release layer granules may be preferably 10 to 70 mg, and more preferably 30 to 50 mg.

At this time, the content of levopropizine in the immediate-release layer granules can be adjusted according to symptoms, but should be at least 10 mg or more, and it is difficult to expect pharmacological activity when it is less than 10 mg. On the other hand, even if it exceeds 70mg, it is difficult to expect any further improvement in pharmacological effects, and side effects may occur.

On the other hand, the sustained-release layer granules contain levopropizine, a release-controlled polymer, a binder and a lubricant, and the drug is maintained for a long period of time at a slow rate by the release-controlled polymer and other excipients. At this time, the active ingredient of levodropropizine in the sustained-release layer granules may contain the same or greater amount as the immediate-release layer, and specifically 20 to 80 mg.

Meanwhile, the disintegrating agent of the immediate-release layer granules may be used by selecting one or a mixture of two or more from the group consisting of sodium starch glycolate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, and crospovidone. The disintegrant is to increase the disintegration rate of the immediate-release layer to achieve rapid pharmacological activity, and in addition to the above-described disintegrant, an excipient having an equivalent action known in the art may be used.

In addition, the lubricant may be one or two or more selected from the group consisting of magnesium stearate, light anhydrous silicic acid, talc, and sodium stearyl fumarate, and in addition, by selecting a suitable one of lubricants known in the formulation field Can be used.

The sustained-release layer granules may contain a binder, wherein as a binder, one or two selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetate, copovidone, and ethylcellulose The above mixture can be used.

In particular, the sustained-release layer granules may contain a release-controlling polymer for controlling the delayed-release rate of the drug, and the release-controlling polymer is one or two selected from the group consisting of hydroxypropylmethylcellulose, collidone SR, and carbomer. It may be a mixture of the above. Among these, it is more preferable when hydroxypropylmethylcellulose and/or collidone SR are used. On the other hand, it is most preferable to use hydroxypropylmethylcellulose having a high viscosity of 100,000 cps, which can be replaced with Collidone SR (BASF) when used in the same amount.

In this case, it is most preferable when it contains 30 to 60% by weight based on the total weight of the release-controlled sustained-release layer granules. If the content is less than 30% by weight, the drug is released too quickly and the duration of the drug effect is shortened, and if it exceeds 60% by weight, the pharmacological effect rapidly decreases within a few hours after oral administration. No improved effect can be expected compared to the formulation.

The sustained-release layer granules and the immediate-release layer granules prepared by the above method are tableted using a tableting machine so that the hardness is 5 to 18kg/cm2.

At this time, it is preferable to perform the tableting at the lower main pressure position 7 to 12 mm. When the lower main pressure position is less than 7 mm, the tableting pressure becomes too high, and the tablet may collapse during manufacture. In addition, the hardness of the prepared tablet may be too high to exceed 18 kg/cm 2, and in this case, the dissolution of the drug is delayed, making rapid pharmacological effect difficult to be expressed. On the other hand, if the lower position of the main pressure exceeds 12 mm, the stability of the tablet is deteriorated due to high friability, and it is difficult to maintain the effective blood concentration of the drug for a long time.

At this time, the order of tableting may be selected from the immediate-release layer granules and the sustained-release layer granules. However, as a result of the experiment, when the immediate-release granules are first tableted, the sustained-release layer granules are added to the prepared immediate-release tablet, and then tableted into a two-layer tablet. , The elution rate was more excellent and was preferable.

The total weight of the sustained-release double-layer tablet containing levodropropizine prepared by tableting the immediate-release layer granules and the sustained-release layer granules may be 250 to 350 mg, and preferably 270 to 320 mg. If the weight is less than the above range, stability is deteriorated, such as cracks in the tablet during tableting, or peeling occurs even after tableting. In addition, when the amount exceeds 350mg, not only does it negatively affect the dissolution rate, but also increases the size of the dosage form, which may deteriorate medication convenience.

The weight of the immediate-release granules and the sustained-release granules among the total weight of the tablet is a relatively large weight of the immediate-release granules, and in this case, the weight ratio of the immediate-release granules and the sustained-release granules is preferably 1.5:1 to 2.5:1. The ratio is an optimum weight ratio in consideration of the tabletting properties and dissolution characteristics of the tablet, and if it is out of this ratio, cracks may occur in the tablet during tableting, or the dissolution characteristics may deteriorate after manufacture.

Meanwhile, the turret speed of the tablet press in step s3 is preferably 12 to 28 rpm, more preferably 15 to 25 rpm, and most preferably 21 to 25 rpm. If the turret speed exceeds 25 rpm, the granules of the tablet may not be sufficiently filled in the tablet press, resulting in a decrease in hardness or friability, and may be unsuitable due to poor formulation uniformity. Conversely, when the turret speed is less than 12 rpm, the production speed in the production process becomes slow, and efficient productivity cannot be secured.

With respect to the above manufacturing method, the hardness of the sustained-release double-layer tablet containing levodropropizine may be 5 to 18kg/cm2, more preferably 8 to 15kg/cm2. When the hardness is low below the above range, stability during storage and transport is deteriorated, and when the hardness exceeds the above range, the dissolution may not be uniform and the pharmacological effect may be reduced. Specifically, when the hardness is too low, such as less than 5kg/cm2, the tablet may not be formed or be easily crushed, and abrasion may appear unsuitable. On the other hand, when the hardness exceeds 18kg/cm2 and is too high, the dissolution of the tablet is slowed, and the target dissolution standard cannot be met outside the target optimum dissolution rate range.

Hereinafter, an example and a comparative example will be described in detail with respect to the manufacturing method of the sustained-release double-layer tablet of levodropropizine of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited by the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

Preparation of immediate-release layer and sustained-release layer granules

First, an immediate-release layer granules and a sustained-release layer granules were prepared according to the above composition of the present invention. The detailed composition is shown in Table 1 below.

division	purpose	ingredient	Content(mg)
Slow-release granules	chief ingredient	Levodropropizine	45.0
	Excipient	Microcrystalline cellulose	6.8
	Release Control Polymer	HPMC 2208 (Viscosity 100,000 cps)	50.0
	Binder	PVP K-90	2.7
	Lubricant	Magnesium stearate	1.7
Immediate release granules	chief ingredient	Levodropropizine	45.0
	Excipient	Lactose hydrate	67.0
	Excipient	Microcrystalline cellulose	67.0
	Disintegrant	Sodium starch glycolate	7.5
	Lubricant	Magnesium stearate	1.9
Total weight	-	-	294.6

Formulation experiment according to the order of tableting (compressed in the order of sustained-release layer and immediate-release layer)

The sustained-release granules prepared according to the composition of Table 1 were first filled in a double tablet tablet press and tableted, and then the immediate-release granules were again filled and tableted on the prepared sustained-release tablet to prepare a two-layer tablet. The turret speed was set to 21 rpm, and the lower position of the main pressure was prepared by differently as shown in Table 2 below, and then the hardness and friability were measured for the prepared tablets (the friability was 1% after 100 rotations for 40 tablets). The following were determined to be suitable).

division	Main pressure lower position (mm)	Hardness (kg/cm2)	Masondo
Comparative Example 1	13.26	4	incongruity
Comparative Example 2	11.26	8	incongruity
Comparative Example 3	9.26	12	incongruity
Comparative Example 4	7.26	15	fitness
Comparative Example 5	5.26	18	fitness

6 tablets of each of Comparative Examples 4 and 5 in which the friability was appropriate were prepared, and 900 mL of water was used as an elution solution, and a dissolution test was conducted at 50 rpm using a sinker according to the second method of dissolution test method among general test methods of the Korean Pharmacopoeia. And the results are shown in Table 3 below.

Time min	Comparative Example 4		Comparative Example 5
	Dissolution rate (%)	Deviation	Dissolution rate (%)	Deviation
0	0	0	0	0
30	45.7	1.9	42.8	2.7
60	55.3	3.2	53.9	2.5
120	59.6	3.3	58.7	4.6
240	80.3	5.2	75.8	1.8
360	90.6	4.1	84.3	3.7
480	93.1	3.9	90.1	2.5
Judgment	incongruity		incongruity

As shown in Table 3, the degree of friability was somewhat large and the dissolution rate was insufficient even after 6 hours, making it difficult to simultaneously expect high stability and excellent dissolution rate.

Formulation experiment according to the order of tableting (compressed in order of immediate release layer and sustained release layer)

Next, the immediate-release granules prepared according to the composition of Table 1 were first filled in a double tablet tablet press and tableted, and then the sustained-release granules were again filled on the prepared immediate-release tablet and tableted to prepare a two-layer tablet. After manufacturing at different positions under the main pressure as shown in Table 4 below, hardness and friability were measured for the prepared tablets (a friability of 1% or less after 100 rotations for 40 test tablets was determined to be suitable) .

division	Main pressure lower position (mm)	Hardness (kg/cm2)	Masondo
Comparative Example 6	13.26	4	incongruity
Example 1	11.26	8	fitness
Example 2	9.26	12	fitness
Example 3	7.26	15	fitness
Comparative Example 7	5.26	18	fitness

After preparing 6 tablets each for Examples 1 to 3 and Comparative Example 7 in which the friability was appropriately shown, 900 mL of water was used as an elution solution. The dissolution test was performed, and the results are shown in Table 5 below.

Time min	Example 1		Example 2		Example 3		Comparative Example 7
	Dissolution rate (%)	Deviation	Dissolution rate (%)	Deviation	Dissolution rate (%)	Deviation	Dissolution rate (%)	Deviation
0	0	0	0	0	0	0	0	0
30	58.4	4.4	54.9	3.7	50.1	1.8	46.3	2.3
60	66.3	2.3	63.7	2.5	62.9	3.1	55.7	3.9
120	78.1	3.1	70.2	1.9	65.8	3.6	59.3	4.1
240	90.8	1.5	82.5	3.3	80.3	2.8	70.5	2.9
360	93.7	2.6	92.4	4.2	88.9	4.1	85.1	3.6
480	96.1	3.6	95.7	2.7	91.5	1.9	90.4	4.8
Judgment	fitness		fitness		fitness		incongruity

As shown in Table 4, in the case of Examples 1 to 3, not only excellent friability, but also excellent dissolution rate, showed a suitable formulation.

Formulation experiment according to turret speed

* Based on the experimental results of Examples 1 to 3 described above, abrasion degree and formulation uniformity were tested by varying the turret speed of the tablet press at a position of 9.26mm under the main pressure where the best effect was shown. As shown in Table 6, a two-layer tablet was prepared by first tableting the immediate-release layer while controlling the turret speed in the range of 15 to 35 rpm, and then filling and tableting the sustained-release layer granules. I did the test.

division	Turret speed (rpm)	Masondo	Formulation uniformity test
Example 4	15	fitness	fitness
Example 2	21	fitness	Suitable (excellent)
Example 5	25	fitness	Suitable (excellent)
Comparative Example 8	31	fitness	incongruity
Comparative Example 9	35	incongruity	-

As shown in Table 6, in the case of Examples 2, 4 and 5 having a turret speed of 15 to 25 rpm, the friability and uniformity of the formulation were suitably shown, and in particular, Examples 2 and 5 having a turret speed of 21 to 25 rpm. In the case of, the formulation uniformity was more excellent.

Claims (14)

1. Preparing immediate-release granules containing levodropropizine, a disintegrant and a lubricant (s1);

   Preparing a sustained-release layer granules containing levodropropizine, a release-controlled polymer, a binder, and a lubricant (s2);

   A method for producing a sustained-release double-layer tablet containing levodropropizine comprising the step (s3) of tableting the sustained-release layer granules and the immediate-release layer granules to a tablet hardness of 5 to 18 kg/cm 2.
2. The method of claim 1,

   The tableting of step s3 is a method for producing a sustained-release two-layer tablet containing levodropropizine that is performed at a lower position of 7 to 12 mm under the main pressure.
3. The method of claim 1,

   The method for producing a sustained-release double-layer tablet containing levodropropizine, wherein the content of levodropropazine in the immediate-release layer granules is 10 to 70mg.
4. The method of claim 1,

   The method for producing a sustained-release double-layer tablet containing levodropropazine, wherein the sustained-release layer granule has a levodropropazine content of 20 to 80 mg.
5. The method of claim 1,

   The disintegrant of the immediate-release layer granules contains levodropropazine, which is one or a mixture of two or more selected from the group consisting of sodium starch glycolate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, and crospovidone. Manufacturing method of sustained-release two-layer tablet.
6. The method of claim 1,

   The lubricant is one or two or more selected from the group consisting of magnesium stearate, light anhydrous silicic acid, talc, and sodium stearyl fumarate. Method for producing a sustained-release double-layer tablet containing levodropropizine.
7. The method of claim 1,

   The binder is one or a mixture of two or more selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetate, copovidone, and ethylcellulose. Method for producing a two-layer tablet.
8. The method of claim 1,

   The release-controlling polymer is a method for producing a sustained-release two-layer tablet containing levodropropazine, which is one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, collidone SR, and carbomer.
9. The method of claim 1,

   The method for producing a sustained-release two-layer tablet containing levodropropizine, wherein the release-controlling polymer is contained in an amount of 30 to 60% by weight based on the total weight of the sustained-release layer granules.
10. The method of claim 1,

    The total weight of the sustained-release two-layer tablet containing levodropropizine is 250 to 350mg of the method for producing a sustained-release two-layer tablet containing lepodropropizine.
11. The method of claim 1,

    The weight ratio of the immediate-release layer granules and the sustained-release layer granules is 1.5:1 to 2.5:1, wherein the method for producing a sustained-release two-layer tablet containing levodropropizine.
12. The method of claim 1,

    In the step s3, the turret speed of the tablet press is 12 to 28 rpm. The method for producing a sustained-release double-layer tablet containing levodropropizine.
13. The method of claim 1,

    In the step s3, the immediate-release layer granules are first filled in a tablet press to prepare an immediate-release layer tablet, and then the sustained-release layer granules are additionally filled in the tablet press and tableted to prepare a two-layer tablet containing levodropropazine. Method of manufacturing.
14. A sustained-release double-layer tablet containing levodropropazine prepared by the method of claim 1.

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