KR102428859B1 - Pharmaceutical composition for oral administration to prevent or treat diseases of the digestive system with safety - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising guayacol as an active ingredient, and by using guayacol as an active ingredient, it can replace the existing creosote, which has a risk of toxicity, to secure stability and It is designed to be easily manufactured for oral administration without using a facility, so it is very excellent in terms of economy and productivity.

Description

Pharmaceutical composition for oral administration to prevent or treat diseases of the digestive system with safety secured {Pharmaceutical composition for oral administration to prevent or treat diseases of the digestive system with safety}

The present invention relates to a pharmaceutical composition for oral administration for the prevention or treatment of diseases of the digestive system with safety secured, an oral preparation using the pharmaceutical composition, and a method for preparing the same.

Jungrohwan ^® is a dragee or pill formulation containing creosote, yellow lily, licorice, dermis, hyangbuja/or chrysanthemum powder as the main active ingredient and has been used as an antidiarrheal drug for stomach upset and diarrhea It is an over-the-counter medicine.

Creosote, one of the main active ingredients, includes coal tar creosote, which is a by-product when coal is carbonized to produce coal tar or natural gas, and wood creosote obtained by carbonizing wood tar. The main chemical substances are polycyclic aromatic hydrocarbons (PAHs). ), phenol, cresol, etc. It is a substance composed of a mixture of up to several dozen phenolic compounds. In pharmaceuticals, wood creosote is used as a colorless to yellow liquid, with a characteristic pungent odor and sharp burnt taste, which gives unique (unpleasant to some patients) olfactory features to commercially available products and has excellent antibacterial effect. It has been used as a disinfectant or laxative. In the past, wood creosote was used to treat leprosy, pneumonia, and tuberculosis, but now it has been almost stopped due to safety issues and is treated as a wood preservative in most countries. Among the phenolic compounds of creosote, the ingredient that is most concerned about safety is cresol, which is also the source of the disgusting odor emanating from Jeongrohwan ^® . ^Cresol is a suspected carcinogen designated by the U.S. Environmental Protection Agency (EPA) and has the potential to cause gastrointestinal damage when taken orally. Concerns have been raised that the amount of cresol in oat may exceed 7 to 10 times the MRL. In addition, the phenol contained in creosote is known to cause irregular breathing, muscle weakness and convulsions, competition, coma, and respiratory arrest as acute toxicity symptoms. Although the therapeutic benefit as a drug is greater than the fear of side effects due to its excellent antibacterial effect, the demand for safer drugs has continued.

In addition to creosote, JEONGROHWAN ^® contains medicinal herbs such as yellow lily, licorice, dermis, and Hyangbuja or Hyeoncho as herbal ingredients to have a pharmacological effect on bacterial stomach upset and diarrhea. it was The complex herbal composition of yellow lotus, licorice, dermis, Hyangbuja or Hyeoncho used in Jungrohwan ^® is a combination of the antibacterial and anti-inflammatory action of yellow lotus, digestion promotion and expectoration action of the dermis, and the antibacterial and antifungal action of Hyangbuja and Hyeoncho. Working together, they were particularly effective against bacterial diarrhea. However, in recent years, the storage and hygiene of drinking water and food has been significantly improved compared to the past, and digestive problems caused by stress, irregular lifestyles, lack of exercise, and fast food, rather than stomach and diarrhea caused by bacteria, are becoming a problem. Therefore, the complex composition of creosote and herbal medicine used in Rohwan Jeong ^® has excellent efficacy in bacterial diarrhea, but there is a problem that it is difficult to expect optimal pharmacological efficacy for modern people's digestive disorders along with concerns about carcinogenic toxicity.

Among the various phenolic substances of creosote, it contains guaiacol, a component that has an antibacterial effect and is not toxic. Guayacol [C ₇ H ₈ O ₂ , molecular weight: _124.14 ] is a precursor of various fragrances such as eugenol. Therefore, it can be considered as a drug that can replace creosote as a safe drug without risk. Guayacol has a melting point of about 28 °C and is mainly liquid at room temperature, but has a saturated vapor pressure of 0.11 mmHg (25 °C), 39 mmHg (51 °C) and 58 mmHg (75 °C), 23.88 mmHg (25 °C) of water and 23.8 mmHg (25 °C) of ethanol. ℃), it is quite volatile compared to ethanol, and at 51°C, it is a more volatile liquid than ethanol at 25°C.

To make a solid preparation such as a tablet using volatile liquid substances such as creosote or guaiacol, the liquid substance is diluted with other solid excipients or adsorbed to a porous solid excipient to be powdered, and then mixed with other excipients to form a tablet. processing methods have been used. Patent Document 1 discloses a method for preparing an oral tablet by encapsulating creosote, a volatile liquid material, in beta-cyclodextrin and then wetting it with colloidal silicon dioxide powder. However, this method is a method of inclusion of molecules in the cyclic oligosaccharide structure of beta-cyclodextrin. Due to the limitation of the size of the ring structure, the inclusion compound is formed in a molar ratio of almost 1:1 with the target inclusion compound, which is much larger than the amount of the target material. It is difficult to obtain a tablet weight suitable for taking due to the need for heavy beta-cyclodextrin. The actual molecular weight of 1 mole of beta-cyclodextrin is 1135, which is 9.14 times that of guaiacol 124.14, and an amount corresponding to about 10 times is required for inclusion. In Patent Document 2, wet granulation film-coated tablets using magnesium metasilicate aluminate containing choline alfoscerate as an active ingredient, while in Patent Document 3, wet granulation using a pharmaceutically active ingredient, magnesium metasilicate aluminate and calcium silicate. Disclosed is an oral pharmaceutical composition for matcha pe.

However, among the above conventional formulations, the method using beta-cyclodextrin requires a large amount of beta-cyclodextrin for inclusion, the manufacturing process is complicated, and special equipment (eg, inclusion tank and solvent drying device) Not only does it require , but there is a problem that it is difficult to apply to the production site due to increased manufacturing cost, and the method according to Patent Documents 2 and 3 uses a wet granulation process, so there is a problem in that the potency of volatile substances is lost during the drying process. have.

Therefore, it is necessary to find a safe and effective substance that can replace creosote, which has a risk of toxicity, and to develop an oral dosage form that can be formulated for a composition of an oral dosage form and the substituted volatile liquid active substance for formulating it.

Domestic registered patent 10-0200245 Domestic registered patent 10-1556568 Domestic registered patent 10-1203186

Accordingly, the present inventors have completed the present invention by developing a pharmaceutical composition capable of formulating guaiacol, a volatile liquid substance that can replace creosote, which has a risk of toxicity, into an oral dosage form.

Therefore, the present invention as an active ingredient guaiacol, hwangryun powder, hwangbaek extract, licorice powder and dermis extract; An object of the present invention is to provide a pharmaceutical composition for oral administration comprising magnesium aluminometasilicate as a stabilizer.

The present invention as an active ingredient guaiacol, hwangryeon powder, hwangbaek extract, licorice powder and dermis extract; And it relates to a pharmaceutical composition for oral administration comprising magnesium aluminometasilicate as a stabilizer.

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

All technical terms used in the present invention, unless otherwise defined, have the same meaning as commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention. The contents of all publications incorporated herein by reference are hereby incorporated by reference in their entirety.

The present inventors discovered that guaiacol has antibacterial activity like creosote, but does not have a toxicity issue, and has no irritating odor compared to creosote's unique smell of meth, so it is a safe alternative drug while improving patient compliance. . In addition, the complex herbal composition of yellow lotus, licorice, dermis, Hyangbuja or Hyeoncho previously used in Jeongrohwan ^® combines the antibacterial and anti-inflammatory action of yellow lotus, digestion promotion and expectoration action of the dermis, and the antibacterial and antifungal action of Hyangbuja and Hyangbuja or Hyeoncho. It was effective against bacterial diarrhea by working with sour. However, according to the principle of oriental medicine, in addition to the antifungal and anti-inflammatory effects, Hwangbaek extract, which is effective for anorexia and indigestion as a stomach medicine, is added, and the dermis extract, which promotes digestion and bile secretion, is strengthened and used together with guaiacol. If it is, it was found that it could be effective in relieving bacterial diarrhea and in the symptoms of digestive disorders such as indigestion and body discomfort that can occur in modern people's eating habits and lifestyle.

In addition, guaiacol, an active ingredient in the pharmaceutical composition of the present invention, has a melting point of about 28° C., and is mainly liquid at room temperature, and as the temperature increases, its volatility increases. It was necessary to stabilize it so that it does not volatilize. As a result of researching a composition with high productivity and easy to carry out, when a pharmaceutically active ingredient is adsorbed or used together with magnesium aluminometasilicate, powdered and stable tablets of pharmaceutically active ingredients are effectively secured even with a small amount found that it can be done.

Accordingly, the present invention provides an oral pharmaceutical composition in which the pharmaceutically active ingredient guaiacol is adsorbed with magnesium aluminometasilicate and adsorbed with a pharmaceutically acceptable carrier, in which the volatile active ingredient is stabilized, and an oral pharmaceutical composition using the same provide formulations for

Since the oral preparation of the present invention is prepared by adsorption, it can be used immediately without dissolving the liquid active ingredient in a solvent, does not need to be dried, and has a simple production process, which is advantageous for industrial application due to high economic efficiency and productivity There are advantages. In addition, due to the strong adsorption power of magnesium metasilicate aluminate, the volatilization of guayachol is suppressed and the potency is well preserved, and at the same time, the expression of the specific odor of the drug is suppressed, so there is no objection when taking the drug. Additionally, metasilicic acid The gastric mucosa protective effect can also be obtained due to the gastric acid neutralizing ability of magnesium aluminate.

"Magnesium aluminometasilicate" is a white powder, also called Silodrate or Simaldrate, represented by the formula Al ₂ O ₂ .2Mg.3O ₃ Si. It is a white powder, insoluble in water, and has hygroscopicity at a relative humidity of 70% or more. It is used as an excipient in a solid formulation to improve powder flowability, and Neusilin (Fuji Chemical Industry) is available as a representative commercially available formulation.

The content of magnesium metasilicate aluminate in the composition may be appropriately selected depending on the type of liquid pharmaceutical active ingredient, dosage form, etc., but preferably 40 to 300 parts by weight based on 100 parts by weight of guaiacol. If its content is less than 40 parts by weight, there is a problem that the liquid active ingredient cannot be sufficiently powdered. there is a problem.

In the pharmaceutical composition according to the present invention, hwangryeon powder was prepared by grinding hwangryeon into a coarse powder, and in this example, it was obtained from Cage Cyebon Co., Ltd. or Kyungil Pharma Co., Ltd. and used.

It is preferable to use 20 to 80 parts by weight or 40 to 70 parts by weight of the yellow lily powder based on 100 parts by weight of guaiacol. When its content is less than 20 parts by weight, there is a problem that the effect of the branch and intestines is insufficient. there is a problem.

Hwangbaek extract powder in the pharmaceutical composition according to the present invention is prepared by pulverizing yellow white to adjust, adding 5 to 10 times water, extracting it at 80 to 100 ° C, and then concentrating the filtrate under reduced pressure to make a powder. It was obtained from Bio-X Co., Ltd. and used.

The yellow white extract powder is preferably used in an amount of 120 to 200 parts by weight or 140 to 170 parts by weight based on 100 parts by weight of guaiacol. When its content is less than 120 parts by weight, there is a problem in that the anti-inflammatory and bile secretion promoting action is lowered. has a problem

Licorice powder in the pharmaceutical composition according to the present invention was prepared by pulverizing licorice into a coarse powder, and in this example, it was obtained and used from Cage Cyebon Co., Ltd. or Kyungil Pharmaceutical Co., Ltd.

The licorice powder is preferably used in an amount of 20 to 80 parts by weight or 40 to 70 parts by weight based on 100 parts by weight of guaiacol. When its content is less than 20 parts by weight, there is a problem in that the effect of suppressing gastritis and gastric ulcer and the effect of harmonizing all drugs is lowered, and when it exceeds 80 parts by weight, the size of the dosage form increases or the number of unit dosage forms to be taken increases, so that the patient There is a problem that worsens medication compliance.

The dermis extraction powder of the pharmaceutical composition according to the present invention is prepared by pulverizing the dermis, adding 5 to 10 times of water, extracting it at 80 to 100° C., and then concentrating the filtrate under reduced pressure to make a powder. It was obtained from Borak Fragrance and used.

The dermis extract powder is preferably used in an amount of 10 to 60 parts by weight or 20 to 50 parts by weight based on 100 parts by weight of guaiacol. When its content is less than 10 parts by weight, there is a problem in that the promoting action of bile secretion is lowered. have.

The pharmaceutical composition according to the present invention may be used for preventing or treating diseases of the digestive system.

As used herein, the term "digestive system disease" is a disease occurring in the digestive system such as the stomach and intestines, and may be one or more selected from the group consisting of indigestion, poor eating, abdominal pain, gastritis, gastric ulcer, enteritis, intestinal obstruction, stomach upset and diarrhea. have.

In addition, the present invention includes an oral formulation comprising the pharmaceutical composition.

The oral preparation is preferably a tablet or pill.

In the oral formulation according to the present invention, guaiacol is preferably 300-600 mg based on a daily dose, and the daily dose of yellow lotus powder, yellow white extract powder, licorice powder and dermis extract powder is 150 to 750 mg of yellow lotus powder, Hwangbaek extract powder 900 to 4,500 mg, licorice powder 150 to 750 mg, and dermis extract powder 500 to 2,500 mg. In particular, the oral formulation of the present invention may be administered in divided doses 1 to 3 times a day, more preferably 1 to 4 tablets are administered at a time in the case of film-coated tablets, and 1 to 3 tablets are administered at a time in the case of pills. can

The pharmaceutically active ingredient also preferably has a manufacturing process suitable for formulation into the oral dosage form desired in the present invention. For example, since the composition of the present invention undergoes an adsorption process, it is required that loss due to volatilization does not occur by undergoing a wet granulation process or a drying process. In particular, when formulated into tablets or pills, it is preferable that the pharmaceutically active ingredient has stable properties from frictional heat caused by pressure during compression molding by a tablet machine or friction during pill injection molding.

As used herein, the term "pharmaceutically acceptable carrier" is used to refer to any component other than a pharmaceutically active ingredient and magnesium metasilicate added for odor masking. A "pharmaceutically acceptable" carrier does not cause undesirable pharmaceutically changes by interacting with other components present in the composition (e.g., between carriers or between an active pharmaceutically active ingredient and a carrier). It means that the character does not The choice of the pharmaceutically acceptable carrier may depend on factors such as the nature of the particular dosage form, the mode of administration, the effect of the carrier on solubility and stability.

In one embodiment, the pharmaceutically acceptable carrier included in the composition may be one or more selected from diluents, binders, lubricants (or lubricants), disintegrants, stabilizers, solubilizers, sweeteners, colorants, and flavoring agents. However, it is not limited thereto.

In the present invention, the excipient may be used in an amount of 20% to 80% by weight with respect to 100% by weight of the total pharmaceutical composition, and for tableting and maintaining quality, for example, 40% to 60% by weight based on 100% by weight of the total composition % by weight.

the present invention

Adsorbing guaiacol, a volatile liquid active material, on magnesium aluminometasilicate to prepare an adsorbate; and

Mixing the adsorbate with the granulate containing the extract powder, yellow lily powder, licorice powder, dermis extract powder and a pharmaceutically acceptable carrier

It includes a method for preparing an oral formulation comprising a.

The oral tablet of the present invention is prepared by adsorption of guaiacol and magnesium metasilicate as the pharmaceutically active ingredients.

As used herein, the term “adsorption” refers to a technique in which the component material constituting the phase is concentrated at the interface when two phases are in contact. It has the advantage of preventing separation of components by maintaining an intact form even after adsorption. It is understood that in the composition according to the present invention, the stability and odor masking of the volatile pharmaceutically active ingredient are effects caused by the interaction of the magnesium metasilicate with the active ingredient in the adsorption step.

Small scale production of adsorption can be carried out by mixing the materials in a mortar or stainless steel vessel and then filtering through a sieve. In the case of larger quantities, a double shell blender, a double cone blender, a differential mixer, a rotary granulator, a high-shear mixer, a spray dryer, and a fluidized bed granulator can be used. A typical adsorption method is described in Pharmaceutical Dosage Forms: Tablets (Volume 1). Ed. H.A. Lieberman, L. Lachman. J.B. Schwartz (1990), Marcel Dekker Inc., New York and Basel, pp. 10-13].

Since the formulation for oral administration according to the present invention is prepared by an adsorption method, drying of the volatile pharmaceutically active ingredient is not used, and thus it is preferable to apply it to a volatile drug.

In addition, since an excess of solvent is not used and a process of drying the excess solvent is not required, productivity is high and economical, and thus it can be industrially applied.

As described above, the pharmaceutical composition according to the present invention is safe while using guaiacol as an active ingredient in order to eliminate the toxicity concerns of creosote, and is effective for anorexia and indigestion along with licorice and yellow lichen. The dermis, which has the action of promoting digestion and bile secretion, is combined, so it is effective in preventing or treating diseases of the digestive system of modern people. In particular, the volatile guaiacol in the present invention can be prepared simply as an oral dosage form using magnesium aluminate metasilicate without using an expensive special manufacturing facility, and the stability of the active drug is secured, and the existing Creoso The unpleasant odor of oats can be excluded, thereby improving the patient's medication compliance. In addition, it is advantageous for industrial application due to the high import substitution effect and high economic efficiency and productivity by replacing the raw materials that were entirely dependent on imports from China with localizable raw materials, and it can be manufactured as an oral dosage form with excellent pharmaceutical properties. .

1 is a photograph showing the form of guaiacol [left: liquid guayacol, middle: agglomeration when a small amount of stabilizer is used, right: powder form when an appropriate amount of stabilizer is used].
2 shows the stability test results of guaiacol for the formulations prepared according to Examples 1-4 and Comparative Examples 1-3.

Advantages and features of the present invention, and methods of achieving them, will become apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be embodied in various different forms, and only these embodiments make the disclosure of the present invention complete, and common knowledge in the technical field to which the present invention pertains It is provided to fully inform those who have the scope of the invention, and the present invention is only defined by the scope of the claims.

Preparation Example 1: Preparation of Hwangbaek Extract Powder (Hwangbaekex Acid)

Yellow white was pulverized to adjust, 5 to 10 times the amount of water was added, extracted at 80-100° C., and the filtrate was concentrated under reduced pressure to obtain a powder.

Preparation Example 2: Preparation of yellow lily powder

It was manufactured by pulverizing yellow lotus into a coarse powder, and it was purchased and used by Keiji Cyebon Co., Ltd. or Kyungil Pharm.

Preparation Example 3: Preparation of licorice powder

It was prepared by pulverizing licorice and making it into a coarse powder, and it was purchased and used by Keiji Cyebon Co., Ltd. or Kyungil Pharm.

Preparation Example 4: Preparation of Dermal Extract Powder (Dry Dermal Extract)

The dermis was pulverized to adjust, and 5 to 10 times the amount of water was added, extracted at 80 to 100° C., and the filtrate was concentrated under reduced pressure to obtain a powder.

Examples 1-4 and Comparative Examples 1-4: Guayachol-containing film-coated tablet preparation

In order to evaluate the physical properties and stability of tablets using the adsorbate of guaiacol and magnesium metasilicate aluminate, film-coated tablets were prepared by the following process.

First, in a speed mixer, Hwangbaekex acid, Hwanglily powder, licorice powder, dermis dry extract, microcrystalline cellulose, and povidone were added, mixed, and then ethanol was added and kneaded to form granules, and then placed in a dryer and dried. Separately, guaiacol was mixed with magnesium metasilicate aluminate in a stainless steel container to prepare an adsorbate in an amount of about 0.4 to 1.4 parts by weight based on 1 part by weight of guaiacol as shown in Table 1 below. The dried product was pulverized and sized in a 1 mm sizing net, and the adsorbate was added together with a disintegrant and a lubricant and mixed in a double cone mixer. The mixture was compressed on a rotary tablet press and compressed into an appropriate form to prepare a tablet having an appropriate level of hardness of 70N for an oral solid preparation.

Tablets were coated by applying about 10% of the total tablet weight using a conventional commercial film coating base to prepare film-coated tablets.

Comparative Examples 1-3: Guayachol-containing film-coated tablet preparation

For comparison, film-coated tablets of Comparative Examples 1 to 3 were prepared in the same manner as in Examples 1 to 4, except that colloidal silicon dioxide, cross-linked polyvinylpyrrolidone and lactose were used as stabilizers (adsorbents).

Experimental Example 1: Confirmation of volatilization of guaiacol

In order to measure the volatility of the active ingredient guayacol, 10 g of liquid guayacol was placed in an opened vial in a vacuum dryer or hot air dryer, and the weight and content change were observed after drying for 4 hours.

The standard of the vial used in this experiment was a 20ml vial with a surface area of 1.13cm ² of the exposed area and ^a 10ml beaker with a 3.46 cm2.

As confirmed in Table 3 below, guaiacol volatilized over time. In addition, the higher the temperature, the more volatilization, and under the same temperature condition, the more the vacuum state, the more the evaporation amount. In addition, it was confirmed that the greater the surface area of the storage container, the greater the evaporation of guaiacol. It was confirmed that the purity of guaiacol was maintained without change even under dry conditions, and only the weight was reduced.

Experimental Example 2: Powdering and stabilization of volatile liquid guaiacol

In order to powder the liquid guaiacol, an adsorption powder was prepared using magnesium metasilicate aluminate or colloidal silicon dioxide.

Guayacol and the adsorbent were used in a weight ratio of 1:0.4 to prepare an adsorbed powder of Neusirin (magnesium aluminate metasilicate) or colloidal silicon dioxide. The adsorption effect and the volatilization stabilization effect of magnesium metasilicate aluminate were confirmed by putting the adsorption powder into a hot air dryer at 40°C.

In order to confirm the degree of adsorption of guaiacol, as shown in Table 4 below, only the adsorbent was used differently, spread evenly on a petri dish, and exposed to accelerated conditions (45° C., 75% relative humidity) to compare the degree of reduction of guaiacol. The adsorbate using Neusirin had an excellent stabilization effect on volatilization compared to the adsorbate using colloidal silicon dioxide. In order to confirm the effect of stabilizing adsorption under the exposure conditions of the commercial manufacturing process, the adsorbates in Table 4 below were mixed with pharmaceutically acceptable excipients as shown in Table 5 and then compressed on a tableting machine to prepare tablets. As confirmed in Table 6 below, in the tablet of Comparative Example 4, it was confirmed that about 10% of guaiacol was volatilized during the process, and the tablet was poorly formed in the tableting process by guaiacol. On the other hand, the tablet of Example 5 using the neusirin adsorbate shows fluidity and compressibility suitable for tableting, and is stable against volatilization, so that it is manufactured without going through a separate drying process.

Experimental Example 3: Confirmation of the adsorption ratio of guaiacol and neucirin

The optimal ratio with magnesium metasilicate aluminate for powdering guaiacol was confirmed.

The photo on the left of FIG. 1 is guaiacol in liquid form. Table 7 is an experiment to confirm the minimum required amount of neusirin by increasing the amount of neosirin after fixing the amount of guaiacol. As in Comparative Examples 5 and 6, when the amount of noisirin is insufficient upon adsorption of guayacol, as shown in the image located in the center of FIG. However, as in Example 7, even when the amount of noicillin is 300 parts by weight compared to 1 part by weight of guaiacol, as shown in the right photo of FIG. It is easy to inject directly, and only the feeling of powder remains when touched by hand. Based on this result, magnesium metasilicate aluminate for powdering was available in an amount of 0.4 to 300 parts by weight based on 1 part by weight of guaiacol.

Experimental Example 4: Stability evaluation

The formulations prepared according to Examples 1 to 4 and Comparative Examples 1 to 3 were exposed to air at room temperature (25° C., 60% relative humidity) to evaluate the content stability of guaiacol.

It was measured and recorded for 4 weeks with an interval of 1 week using HPLC analysis (FIG. 2).

As a result, the formulations of Examples 1 to 4 were more stable than the formulations of Comparative Examples 1 to 3 and maintained their initial content. Colloidal silicon dioxide of Comparative Example 1 also had a relatively stabilizing effect, but the effect was lower than that of magnesium metasilicate aluminate.

Claims (14)

delete delete delete delete delete delete delete delete delete delete delete delete Adsorbing guaiacol, a volatile liquid active material, on magnesium aluminometasilicate to prepare an adsorbate, and
Mixing the adsorbate with the granulate containing the extract of Hwangbaek, Hwanglily powder, licorice powder, dermis extract and a pharmaceutically acceptable carrier
A method for preparing an oral formulation comprising a.
14. The method of claim 13,
A method for preparing an oral formulation using 40 to 300 parts by weight of a stabilizer based on 100 parts by weight of guaiacol.

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