WO2022114796A1 - Pharmaceutical composition comprising high content of active ingredients derived from natural substances - Google Patents

Abstract

The present disclosure relates to a formulation, preferably a tablet, comprising a high content of herbal extracts of Clematis florida, Trichosanthes kirilowii Maxim, and Prunella vulgaris var. lilacina Nakai as active ingredients useful for treating or alleviating arthritis. The formulation of the present disclosure comprises a high content of active ingredients and has a small size, thereby being very convenient to administer, having a release pattern that can be taken twice a day, and exhibiting excellent release properties, and in particular, there is no significant difference in a dissolution pattern at various pHs, thereby reducing interpersonal and interindividual variations.

Description

Pharmaceutical composition comprising a high content of active ingredients derived from natural products

This application claims priority based on Korean Patent Application No. 10-2020-0159054 filed on November 24, 2020, and all contents disclosed in the specification and drawings of the application are incorporated herein by reference.

The present disclosure relates to a formulation containing a herbal extract of Wiryungseon, Gwalugeun and Hagocho, and relates to a formulation that contains a high content and exhibits a desirable release pattern and can be taken twice a day. The present disclosure also relates to a formulation capable of reducing inter-individual and inter-individual variation because there is no significant difference in dissolution pattern at various pHs.

Osteoarthritis, also called degenerative arthritis, is the most common arthritis in adults. Osteoarthritis patients are rapidly increasing as an aging society progresses, leading to a decrease in the individual patient's quality of life as well as social and economic losses.

Arthritis refers to a disease that causes inflammation in the joints, and there are many types. The most common arthritis is osteoarthritis, and other types include rheumatoid arthritis, gout, and psoriatic arthritis. The cause of each arthritis is different, but the destruction of cartilage tissue is the same.

Degenerative arthritis (osteoarthritis) is a representative chronic joint disease that occurs most frequently among arthritis. In degenerative arthritis, the cartilage tissue surrounding the ends of the bones is gradually worn, causing inflammation and severe pain in the joints, and abnormal hardening of the bones under the cartilage. Therefore, the cartilage that cushions the friction caused by the movement of the joint is worn away and severe pain and movement disorders appear when the joint is moved.

Despite many studies to control degenerative arthritis, a fundamental treatment based on the pathological cause of the disease has not yet been developed. -Modifying osteoarthritis drug (DMOAD), etc. are mainly used for anti-inflammatory and pain relief. In addition, chondroprotectors such as hyaluronic acid, glucosamine, and chondroitin have been developed and marketed, but their therapeutic effects have not been established in cartilage protection and regeneration induction.

On the other hand, the complex herbal extracts of Wiryongseon, Gwalugeun, and Hagogi are known to have anti-inflammatory, analgesic, joint protective and immunosuppressive actions, and are widely used as therapeutic agents for osteoarthritis and rheumatoid arthritis.

It is known that the herbal extracts of Wiryongseon, Gwalugeun, and Hagogi contain rosmarinic acid and oleic acid. Rosmarinic acid is known to have antioxidant activity, such as inhibiting lipid peroxidation, inhibiting the biosynthesis of prostacyclin produced as a result of metabolism of arachidonic acid, and scavenging free radicals generated in polynuclear leukocytes. In addition, rosmarinic acid is known to suppress the production of mediators of the inflammatory reaction, anti-inflammatory action against allergic inflammation due to immunomodulatory activity, and the effect of improving blood circulation by inhibiting platelet aggregation and decomposing fibrin.

These herbal extracts may be manufactured into tablets containing a high content, but if the dose is simply increased to increase the medicinal effect, an increase in side effects may appear. In addition, the currently marketed formulations containing the complex herbal extracts of Wiryungseon, Gwalugeun, and Hagocho are to be taken three times a day, so the convenience of taking is inferior.

Therefore, in order to prevent side effects caused by the high content formulation and to increase the convenience of taking, a formulation with delayed release (controlled) may be considered, but the present inventors confirmed through experiments. Several unexpected problems emerged.

Therefore, the problem to be solved by the present disclosure is that while containing Wiryungseon, Gwalugeun and Hagochu extract as active ingredients (particularly high content), the formulation size is small, it is convenient to take, and it has a desirable release pattern, so twice a day It is to provide a preparation, preferably a tablet, which is dosable, exhibits good release properties, and does not substantially change the release pattern in various pH media.

In order to solve the above problems, one aspect of the present invention contains 280-320 mg of herbal extracts of Wiryungseon, Gwalugeun and Hagocho as active ingredients, and croscarmellose sodium, low-substituted hydroxypropyl cellulose or Formulations, preferably tablets, are provided which are characterized by controlled release comprising mixtures thereof.

In a preferred aspect of the present invention, the total content of the active ingredients included in the formulation of the present invention is 40 to 90 wt% (preferably, 50 -90% by weight, more preferably 60-90% by weight).

The present inventors attempted to prepare a twice-daily dosage formulation containing a high content of herbal extracts of Wiryungseon, Gwalugeun and Hagocho, but unexpected problems were found as a result of the study. Most of the disintegrants did not exhibit the desired disintegration effect, and the final dissolution rate was not satisfactory. Of course, it is possible to manufacture a tablet with high disintegration and final dissolution rate by using a large amount of other additives, that is, by reducing the relative content of the extract. However, in this case, the size of one formulation to be taken was too large, which made taking it too inconvenient. That is, it may be because of the specific physical properties of the herbal extracts of Wiryungseon, Gwalugeun and Hagochi, a high content of Wiryyeongseon, Gwalugeun, and Hagochi herbal extracts are included in a high weight % relative to the formulation weight, while at the same time providing a good release pattern and high release properties. It was not easy to achieve.

The present inventors have completed one aspect of the present invention by confirming that these contradictory problems can be resolved by using croscarmellose sodium, low-substituted hydroxypropyl cellulose or a mixture thereof as a disintegrant.

In addition, the solubility of various components included in the herbal extract may be different depending on the pH, so a formulation capable of overcoming this solubility difference is needed. Specifically, in the case of rosmarinic acid, which is a representative medicinal ingredient of the herbal extract of the present invention, the solubility is relatively low at low pH, and thus the release property at low pH is maintained high, and the dissolution variation at various pHs is reduced to reduce the absorption variation between individuals and between individuals. it is important In this aspect, croscarmellose sodium, which is the two disintegrants according to the present invention, and croscarmellose sodium among the low-substituted hydroxypropyl celluloses are more preferable.

As the herbal extract of Wiryyeongseon, Gwalugeun, and Hagogi of the present invention, the extract of 'Wiryeongseon·Gwalugeun·Hagocho 30% ethanol extract (40→1)', which is a yellowish-brown-brown hygroscopic powder, can be used. For example, the herbal extract of Wiryeongseon, Gwalugeun and Hagocho may be a herbal extract prepared according to the method described in Korean Patent Registration Nos. 180567 and 483707 (WO2002-094301 A1).

One aspect of the present invention is also a formulation containing 280-320 mg of 'Wiryeongseon·Gwalugeun·Hagocho 30% ethanol extract (40→1)' extract as an active ingredient, and the content of the active ingredient is the total weight of the uncoated tablet before coating Or 40 to 90% by weight (preferably, 50-90% by weight, more preferably 60-90% by weight) relative to the total weight of the mixture filled in the empty capsule, and is a formulation to be taken twice a day, 37±0.5 In the case of dissolution test under conditions of 900 ml of water medium by paddle test at 50 rpm at ℃, the release of rosmarinic acid is 40-70% at 45 minutes, 75% or more at 90 minutes (more preferably 40- at 45 minutes) 70%, greater than 75% at 90 minutes, greater than 80% at 120 minutes, even more preferably greater than 45-60% at 45 minutes, greater than 80% at 90 minutes, greater than 85% at 120 minutes); Provided is a formulation, preferably a tablet, comprising raw croscarmellose sodium, low-substituted hydroxypropyl cellulose or a mixture thereof (more preferably, croscarmellose sodium) to control the release. .

More preferably, the tablet according to the present invention evaluates the dissolution of rosmarinic acid by the Korean Pharmacopoeia dissolution test method, but at 37±0.5 ° C., a paddle test method at a speed of 50 rpm, pH 1.2, pH 4.0, pH 6.8, and DW In the case of dissolution test for 4 hours under the condition of 900ml medium, the difference between the maximum value and the minimum value is 20% or less when comparing the dissolution values of the four media at 30, 60, 90, 120, 180, and 240 minutes.

One aspect of the present invention is a formulation containing 280-320 mg of herbal extracts of Wiryungseon, Gwalugeun and Hagocho as an active ingredient, and the content of the active ingredient is 40 to 90 based on the total weight of the mixture filled in uncoated tablets or empty capsules before coating % by weight (preferably 50-90% by weight, more preferably 60-90% by weight), it is a formulation to be taken twice a day, and water by a paddle test method at 37±0.5° C. at a speed of 50 rpm During the dissolution test under the conditions of 900ml medium, the release of rosmarinic acid is 40-70% at 45 minutes, 75% or more at 90 minutes, and 80% or more at 120 minutes, and croscarmellose sodium as a disintegrant, low-substituted hydroxy Formulations, preferably tablets, are provided, characterized in that the release is controlled using propylcellulose or a mixture thereof (more preferably croscarmellose sodium). The content of croscarmellose sodium, low-substituted hydroxypropyl cellulose or a mixture thereof is preferably 1-10% by weight relative to the total weight of the mixture filled in uncoated tablets or empty capsules before coating, and 1-8% by weight more preferably, 2-5% by weight is even more preferable.

In one aspect of the present invention, the formulation according to the present invention includes a binder for controlling the release of the active ingredient. Such binders include polyvinylpyrrolidone (eg, Kollidon K30 (viscosity of about 5.5-8.5 cps (20° C., 10% w/v))), ethyl cellulose, ethyl acrylate methacrylate copolymer (eg, , Eudragit L100-55 (viscosity about 50-200cps)), hydroxypropylmethylcellulose (eg, Metolose (viscosity about 100cps (20°C/2% w/v))), hydroxypropylcellulose (eg For example, Nisso HPC-L (viscosity of about 6-10 cps (20° C./2% w/v)), acrylic acid copolymer (eg, Carbomer 971 (viscosity of about 4000-11000 (0.5% w/w))) etc. may be used alone or in combination, and in terms of controlling the release of herbal extracts of Wiryungseon, Gwalugeun and Hagocho to the desired level in the present invention and maintaining high final release properties, ethyl cellulose, ethyl methacrylate Polymers or mixtures thereof are preferred, and ethylcellulose is even more preferred.

As such ethyl cellulose, those having a viscosity of 3-22 mPa.s when measuring the viscosity at room temperature by making a 5 wt% solution with a toluene/ethanol 80:20 (volume ratio) mixed solvent may be used.

0.1-10 wt% of the binder is preferably 0.1-10 wt%, more preferably 0.4-5 wt%, and still more preferably 0.8-3 wt%, based on the total weight of the uncoated tablet before coating.

In one aspect of the present invention, the formulation, particularly the tablet, may optionally further include a pharmaceutically acceptable excipient, adsorbent, lubricant, and the like.

Microcrystalline cellulose, lactose, mannitol, etc. can be used as the excipient, and the content of these excipients is preferably 5-40 wt%, more preferably 10-35 wt%, and 15-30 wt%, based on the weight of the uncoated tablet before coating. is even more preferable.

As the adsorbent, light anhydrous silicic acid (including hydrophobic light anhydrous silicic acid), magnesium aluminum silicate, etc. can be used, and the content of this adsorbent is preferably 0.5-9 wt%, more preferably 1-7 wt%, based on the weight of the uncoated tablet before coating. preferred, 2-5% by weight is even more preferred. The inclusion of such an adsorbent is more preferred for the purposes of the present invention.

As the lubricant, stearyl fumarate, magnesium stearate, stearic acid, talc, etc. can be used, and the content of the lubricant is preferably 0.1-4 wt%, more preferably 0.2-2 wt%, based on the weight of the uncoated tablet before coating. do.

In one aspect of the present invention, the tablet according to the present invention may also be coated for various purposes, such as protection from external impact, appearance, control of release, and the like. For example, the uncoated tablet may be coated using a coating composition including a film former, a plasticizer, an anti-adhesive body, and the like, and the content of the coating is 1-15 wt%, preferably based on the total weight of the uncoated tablet prior to coating. can be coated in an amount of 3-10% by weight.

The formulation according to the present invention is obtained by preparing granules by a wet granulation method using a solvent such as water, ethanol, isopropanol, or a dry granulation method using compression force, and then mixing the granules with post-mixing components such as a disintegrant and a lubricant. It may be manufactured as a tablet or filled into an empty capsule and prepared as a capsule. The formulation according to the present invention may be prepared as a tablet by a direct pressing method without a granule manufacturing process, or may be prepared as a capsule by a method of filling after simple mixing. However, the wet granulation method may be preferable in terms of maintaining the release pattern, which is the object of the present invention, without deviation.

Accordingly, one aspect of the present invention is to prepare granules using a herbal extract, a binder, optionally an adsorbent, optionally a disintegrant; preparing a tablet by post-mixing a lubricant, a disintegrant, etc., which are pharmaceutically acceptable additives, to the granules prepared above and tableting; and optionally coating the tablet.

The present disclosure is a formulation containing a high content of herbal extracts of Wiryungseon, Gwalugeun, and Hagocho, taken twice a day, has a small size, has excellent medication convenience, and exhibits a release pattern suitable for taking twice a day, Provided is a formulation, preferably a tablet, that has excellent release properties and, in particular, has no significant difference in dissolution pattern at various pHs and can reduce inter-individual and inter-individual variation.

The following drawings attached to this specification serve to further understand the technical idea of the present invention together with the contents of the above-described invention, so the present invention should not be construed as limited only to the matters described in such drawings.

1 is a graph showing the dissolution pattern in a pH 1.2 medium for each type of disintegrant.

2 is an experimental result showing that one embodiment according to the present invention exhibits a similar dissolution pattern in various media.

Hereinafter, examples and the like will be described in detail to help the understanding 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 to 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 to which the present invention pertains.

Experimental Example 1: Evaluation of solubility of active ingredients of herbal extracts by pH

Solubility evaluation for each pH of rosmarinic acid, one of the active ingredients of the complex herbal extract, was conducted. The solubility results are shown in Table 1 below.

<Solution Test Method>

1) Prepare pH1.2, pH4.0, pH6.8, and DW.

2) Put 50 mg of rosmarinic acid and each pH solution into a tube, stir and sonicate for 5 minutes.

3) After saturation by stirring at 37 °C and 100 rpm for 24 hours, centrifugation is performed.

4) Take the supernatant and check the solubility after dilution.

	pH 1.2	pH 4.0	pH 6.8	DW
Solubility (mg/mL)	3.25	6.58	6.07	5.85

As shown in Table 1, it was confirmed that rosmarinic acid, one of the active ingredients of the complex herbal extract, had low solubility at pH 1.2, an acidic condition. From these results, it was expected that the release of many components included in the complex herbal extract would vary depending on the pH. In addition, it was found that the releasability in an acidic medium with relatively low solubility should be confirmed first.

Examples 1, 2 and Comparative Example 1: Preparation of complex herbal extracts

Using the contents and ingredients shown in Table 2 below, tablets containing 30% ethanol extract of Wiryyeongseon·Gwalugeun·Hagocho 30% (40→1) extract were prepared. After dissolving ethyl cellulose (binder) in isopropyl alcohol to make a binding solution, the extract and hydrophobic light silicic anhydride were added to the binding solution to prepare wet granules. After that, each disintegrant and stearyl fumarate were mixed and then tableted.

Ingredients (unit: mg)	Example 1	Example 2	Comparative Example 1-1	Comparative Example 1-2	Comparative Example 1-3	Comparative Example 1-4	Comparative Example 1-5	Comparative Example 1-6
herbal extract	300	300	300	300	300	300	300	300
Hydrophobic light anhydrous silicic acid	10	10	10	10	10	10	10	10
ethyl cellulose	20	20	20	20	20	20	20	20
Croscarmellose Sodium	25
Low-substituted hydroxypropyl cellulose		25
Sodium starch glycolate			25
pregelatinized starch				25
crospovidone					25
Carboxymethylcellulose calcium						25
Magnesium metasilicate aluminate							25
Microcrystalline Cellulose								25
Stearyl Fumarate	2	2	2	2	2	2	2	2
tablet total weight	357	357	357	357	357	357	357	357

Experimental Example 2: Evaluation of dissolution in acidic medium by type of disintegrant

The dissolution properties of Examples 1 and 2 and Comparative Example 1 were evaluated according to the dissolution test method of the 12th revision of the Korean Pharmacopoeia. The paddle method was used, the stirring speed was 50 rpm, and the elution temperature was 37.0 ± 0.5 °C. The eluate was carried out at pH 1.2 900ml. In order to improve the stability of the sample solution, it was analyzed after pretreatment with acetonitrile. The dissolution rate was measured by measuring the content of rosmarinic acid, an active ingredient of the herbal extract, over time. The dissolution test results are shown in Table 3 and FIG. 1 below. The content of rosmarinic acid is described in J. Sep. Sci. 2015, 0, 1-8 (“Quality evaluation of Salvia miltiorrhiza Bge. by ultra high performance liquid chromatography with photodiode array detection and chemical fingerprinting coupled with chemometric analysis”).

hours (minutes)	Example 1	Example 2	Comparative Example 1-1	Comparative Example 1-2	Comparative Example 1-3	Comparative Example 1-4	Comparative Example 1-5	Comparative Example 1-6
5	7	6	2	6	7	6	10	8
10	12	10	6	11	12	10	14	12
15	19	12	11	15	18	13	18	15
30	33	21	21	23	28	20	25	21
45	47	32	31	34	40	26	31	26
60	62	49	40	44	47	33	35	30
90	86	83	50	57	62	48	42	36
120	92	93	61	71	73	65	48	42
180	94	96	67	82	84	87	57	53
240	97	98	70	84	86	93	63	61

As shown in Table 3 and FIG. 1, it can be confirmed that in Examples 1 and 2, the dissolution is completely performed under acidic conditions. In contrast, when the disintegrant of Comparative Examples was used, complete dissolution was not performed even if dissolution evaluation was performed for a long time. This is presumed to be due to the physical properties of the extract of the present disclosure, and it appeared that rosmarinic acid, an active ingredient of the herbal extract, was not sufficiently released from the granule residue. The present inventors surprisingly confirmed that sufficient release is possible even from the granular residue when a specific disintegrant is used. It was confirmed that complete release was achieved when the disintegrant was croscarmellose sodium and low-substituted hydroxypropyl cellulose.

In addition, as a result of various evaluations performed by the present inventors, the dissolution pattern as in Example 1 in the case of tablets containing 300 mg of Wiryyeongseon·Gwalugeun·Hagocho 30% ethanol extract (40→1) extract twice a day (eg, 40-70% at 45 minutes, 75% or more at 90 minutes, 80% or more at 120 minutes) was most preferable, and in matching this characteristic dissolution pattern, croscarmellose as a disintegrant Sodium or low-substituted hydroxypropyl cellulose was preferable, and especially croscarmellose sodium was more preferable.

In the case of the disintegrant of Comparative Example 1-4, a high dissolution rate is obtained when a long-term dissolution evaluation is performed, but the initial disintegration effect is low, and a high content of Wiryyeongseon·Gwalugeun·Hagocho 30% ethanol extract (40→1) It was difficult to achieve the dissolution pattern of the formulation taken twice a day while containing the extract at a high ratio.

The properties according to these disintegrants are presumed to be due to the physical properties of the extracts of Wiryungseon, Gwalugeun, and Hagocho, but the present invention is not limited to these theoretical mechanisms.

Example 3: Confirmation of dissolution at various pHs

In the previous experiment, it was confirmed that the solubility of rosmarinic acid, an active ingredient (indicator component) of the herbal extract, varies depending on the pH. Therefore, it is necessary to confirm whether it exhibits a desirable dissolution pattern in a medium of various pH.

Using the contents and ingredients shown in Table 4 below, tablets containing herbal extracts of Wiryongseon, Gwalugeun and Hagocho were prepared. First, ethyl cellulose was dissolved in isopropyl alcohol to make a binder solution, and then the extract and hydrophobic light silicic anhydride were added to the binder solution to prepare wet granules. Microcrystalline cellulose, croscarmellose sodium, and stearyl fumarate were mixed with the prepared wet granules and tableted. The core thus prepared was coated with a coating base.

Ingredients (unit: mg)	Example 3
herbal extract	300
Microcrystalline Cellulose	95
Hydrophobic light anhydrous silicic acid	10
Ethyl Cellulose 4 cps	8
Croscarmellose Sodium	13
Stearyl Fumarate	2
coating base	28
tablet total weight	456

Experimental Example 3: Evaluation of dissolution in various media

The dissolution test was carried out in Example 3 according to the dissolution test method of the 12th revision of the Korean Pharmacopoeia. The paddle method was used, the stirring speed was 50 rpm, and the elution temperature was 37.0 ± 0.5 °C. Eluates were carried out at pH 1.2, pH 4.0, pH 6.8, and 900 ml of DW. In order to improve the stability of the sample solution, it was analyzed after pretreatment with acetonitrile. The dissolution rate was measured by measuring the content of rosmarinic acid, an active ingredient of the herbal extract, over time. The dissolution test results are shown in Table 5 and FIG. 2 below.

hours (minutes)	pH 1.2	pH 4.0	pH 6.8	DW
5	0	5	4	5
10	7	12	13	14
15	14	20	22	20
30	29	44	46	40
45	48	58	60	57
60	62	70	72	71
90	82	85	89	88
120	92	90	95	94
180	93	95	99	98
240	97	96	98	99

As shown in Table 5, Example 3 showed a similar dissolution pattern, that is, a pH-independent dissolution pattern, even though the solubility of rosmarinic acid, an active ingredient of the herbal extract, was different for each pH.

In addition, the tablet of Example 3, which is an aspect according to the present invention, has the desired dissolution pattern (for example, 40-70% at 45 minutes, 75% or more at 90 minutes, and more Preferably, 80% or more at 120 minutes) was confirmed.

Claims (12)

1. It contains 280-320 mg of herbal extracts of Wiryungseon, Gwalugeun and Hagocho as active ingredients, and contains croscarmellose sodium, low-substituted hydroxypropyl cellulose, or a mixture thereof as a disintegrant to control the release. agent that does.
2. According to claim 1, wherein the content of the active ingredient is 40 to 90% by weight, based on the total weight of the mixture before filling the uncoated tablet or empty capsule before coating, the formulation.
3. The formulation of claim 2, wherein the content of the active ingredient is 50 to 90% by weight based on the total weight of the mixture before filling the uncoated tablets or empty capsules before coating.
4. The formulation according to claim 3, wherein the content of the active ingredient is 60 to 90% by weight based on the total weight of the mixture before filling the uncoated tablets or empty capsules before coating.
5. 5. The formulation according to any one of claims 1 to 4, wherein the formulation comprises croscarmellose sodium as a disintegrant.
6. 5. The formulation according to any one of claims 1 to 4, wherein the formulation is a tablet.
7. It is a formulation containing 280-320 mg of herbal extracts of Wiryungseon, Gwalugeun and Hagocho as an active ingredient, and the content of the active ingredient is 40 to 90% by weight compared to the total weight of the mixture before coating and filling uncoated tablets or empty capsules, twice a day It is a drug to be taken,

   In the case of dissolution test under the conditions of 900 ml of water by the paddle test method at 37±0.5 ° C., 50 rpm speed, the release of rosmarinic acid is 40 to 70% at 45 minutes, 75% or more at 90 minutes, 80% or more at 120 minutes is,

   A formulation comprising croscarmellose sodium, low-substituted hydroxypropyl cellulose or a mixture thereof as a disintegrant to control the release.
8. 8. The formulation of claim 7, wherein the disintegrant is croscarmellose sodium.
9. The formulation according to claim 7, wherein the content of the active ingredient is 50 to 90% by weight based on the total weight of the mixture before filling the uncoated tablets or empty capsules before coating.
10. According to claim 1 or 6, wherein the formulation evaluates the dissolution of rosmarinic acid, pH 1.2, pH 4.0, pH 6.8, and DW 900ml medium conditions with a paddle test method at 37±0.5° C., 50 rpm. A formulation with a difference of 20% or less between the maximum and minimum values compared to the dissolution values of 4 media at 30, 60, 90, 120, 180, and 240 minutes during a dissolution test for 4 hours.
11. 11. The formulation of claim 10, wherein the formulation comprises ethylcellulose as a binder.
12. The formulation of claim 11 , wherein the formulation is a tablet.

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