Composition with improved phase stability and dosage recovery, having excellent packing compatibility, and composition for the prevention and treatment of respiratory diseases comprising the same

Abstract

The present invention relates to a pharmaceutical composition having excellent packaging suitability with improved phase stability and volume recovery rate, and a composition for the prevention and treatment of respiratory diseases containing the same. More specifically, the invention relates to a pharmaceutical composition in which phase stability, volume recovery rate, and packaging suitability are simultaneously and significantly improved by controlling the particle size and viscosity of the composition.

Description

Technology Field

[0001] The present invention relates to a composition having excellent packaging suitability with improved phase stability and volume recovery rate, and a composition for the prevention and treatment of respiratory diseases containing the same. More specifically, the invention relates to a composition in which phase stability, volume recovery rate, and packaging suitability are significantly improved simultaneously by controlling the particle size and viscosity of the composition. Background Technology

[0002] Coughing is a symptom commonly associated with the common cold, severe inflammatory respiratory diseases such as asthma, bronchitis, and pneumonia, and postnasal drip. It is an involuntary reflex action for the body's defense, designed to prevent dust, microorganisms, and irritating harmful substances from entering the airways and to remove foreign substances that have entered the bronchi and lungs. If coughing is too severe, it can cause significant discomfort in daily life and may lead to symptoms such as shortness of breath, chest pain, vomiting, and dizziness. Furthermore, in severe cases, frequent coughing can cause damage to the mucous membranes of the pharynx and larynx. Even in the case of a common cold, if appropriate treatment for symptom relief is not provided at the right time, there is a high risk of it progressing into infectious and inflammatory diseases such as upper respiratory infections, bronchitis, and pneumonia; therefore, the use of medication for effective symptom relief and treatment of the underlying cause is crucial.

[0003] Meanwhile, the action of expelling foreign harmful substances through bronchial muscle movements along with saliva is called sputum. If there is an inflammatory reaction in the bronchi or lungs, purulent sputum is produced or inflammation occurs in the airway mucosa. When inflammation occurs in the airway mucosa, secretions increase as a self-regulating physiological phenomenon, and expectorants facilitate the expulsion of these secretions.

[0004] Conventional antitussives include central antitussives such as opioid alkaloids, dextromethorphan, and phenobarbitals, and peripheral antitussives such as sympathomimetic agents or xanthine compounds (aminophylline, theophylline); expectorants include emetic expectorants such as apomorphine and saponins, and proteolytic enzymes such as varidase and chymotrypsin.

[0005] Recently, active research is being conducted on pharmaceuticals exhibiting anti-inflammatory, antitussive, and expectorant effects using pharmaceutical compositions for treating respiratory diseases composed of Pelargonium sidoides.

[0006] Pelargonium sidoides is a plant native to South Africa, and extracts from its roots are known to have excellent preventive and therapeutic effects on acute bronchitis, including not only relief of symptoms such as headache, fever, fatigue, and runny nose, but also antiviral, antibacterial, and antitussive effects.

[0007] Accordingly, Pelargonium sidoides extract has been formulated and commercialized as a natural medicine in the market, including Umkamin Syrup (Hanwha Pharmaceutical, Korea) and Calomin S Tablet (United Pharmaceutical, Korea).

[0008] Among modern people, a disease that simultaneously causes coughing and an increase in the secretion of thick sputum is the common cold, also known as acute viral rhinopharyngitis or acute rhinitis, which occurs when the upper respiratory system, such as the nose or throat, is infected by viruses. Therefore, readily available cold medicines contain both cough suppressants (also called antitussives) and expectorants (sputum expectorants or mucolytics), and representative products include Codeone Forte Syrup (Daewon Pharmaceutical, Korea) and Kofu Syrup (Yuhan Corporation, Korea), which contain dihydrocodeine, dl-methyl ephedrine, chlorpheniramine, and ammonium chloride.

[0009] In order to enhance the effect of treating and preventing respiratory diseases by adding Pelargonium sidoides extract to a pharmaceutical composition containing dihydrocodeine, dl-methyl ephedrine, chlorpheniramine, and ammonium chloride as active ingredients, a syrup formulation made of this combination has been released and has been clinically proven to have additional effects on respiratory diseases.

[0010] On the other hand, while liquid formulations have the advantage of demonstrating rapid efficacy compared to solid formulations and improving medication compliance in infants or elderly patients with difficulty swallowing or dysphagia, they also have disadvantages such as easily becoming unstable, difficulty in proper dose recovery, and deterioration of packaging characteristics due to the physical or rheological properties of the particles constituting the liquid formulation. Prior art literature

[0011] Patent Publication No. 10-2019-0044552 (April 30, 2019) The problem to be solved

[0012] The present invention aims to provide a liquid formulation having improved phase stability, dose recovery rate, and excellent packaging suitability by controlling the particle size and viscosity range of a pharmaceutical composition comprising: Pelargonium sidoides extract; dihydrocodeine or a pharmaceutically acceptable salt thereof, chlorpheniramine or a pharmaceutically acceptable salt thereof, dl-methyl ephedrine or a pharmaceutically acceptable salt thereof, an active ingredient of ammonium chloride, and a thickening agent.

[0013] To this end, the present invention has established conditions in which phase stability, volume recovery rate, and packaging suitability can be simultaneously maximized by controlling the average particle size and viscosity range of particles in a pharmaceutical composition comprising: Pelargonium sidoides extract; dihydrocodeine or a pharmaceutically acceptable salt thereof, chlorpheniramine or a pharmaceutically acceptable salt thereof, dl-methyl ephedrine or a pharmaceutically acceptable salt thereof, an active ingredient of ammonium chloride, and a thickening agent. means of solving the problem

[0014] The present invention relates to a pharmaceutical composition comprising, as an active ingredient, an extract of Pelargonium sidoides; and dihydrocodeine or a pharmaceutically acceptable salt thereof, chlorpheniramine or a pharmaceutically acceptable salt thereof, dl-methyl ephedrine or a pharmaceutically acceptable salt thereof, and ammonium chloride, wherein the composition further comprises a thickening agent, the average particle size of the particles of the composition is less than 210 μm, and the shear rate of the composition is 10 s -1 A composition having improved phase stability and capacity recovery rate and excellent packaging suitability is provided, characterized by a viscosity of 160 to 810 cps as measured.

[0015] The present invention relates to a shear rate of 100 s of the above composition -1 The viscosity measured at may be 150 cps or less.

[0016] The present invention relates to a shear rate of 10 s of the above composition -1 The ratio of average particle size to viscosity measured in may be 1 or less.

[0017] The present invention may include one or more of xanthan gum, guar gum, pectin, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and sodium alginate.

[0018] The present invention relates to a shear rate of 10 s of the above composition -1 The viscosity measured at may be in the range of 200 to 600 cps.

[0019] The present invention relates to a shear rate of 100 s of the above composition -1 The viscosity measured at may be 120 cps or less.

[0020] The present invention relates to a shear rate of 10 s of the above composition -1 The ratio of average particle size to viscosity measured in may be 0.6 or less.

[0021] The present invention may further include a preservative in the above composition.

[0022] The present invention may further include a pH adjuster in the above composition.

[0023] The present invention may further include a sweetener in the above composition.

[0024] The present invention provides a composition for the prevention and treatment of respiratory diseases comprising a composition having excellent packaging suitability while having the improved phase stability and volume recovery rate described above. Effects of the invention

[0025] The composition according to the present invention suppresses phase separation and allows for sufficient discharge from a pouch, thereby significantly improving phase stability and volume recovery rate. The composition according to the present invention has excellent packaging suitability, particularly as it can be filled well without contamination when packaged in a pouch. Specific details for implementing the invention

[0026] The terms used in this invention are used merely to describe specific embodiments and are not intended to limit the invention. The singular expression includes the plural expression unless the context clearly indicates otherwise. In this application, terms such as “to constitute,” “to provide,” “to include,” or “to have” are intended to specify the existence of the features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, and should be understood as not precluding the existence or addition of one or more other features, numbers, steps, actions, components, parts, or combinations thereof.

[0027] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which this invention pertains. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this invention.

[0028] The present invention may include suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions. Pharmaceutical compositions according to the present invention may be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups according to conventional methods. Carriers, excipients, diluents, and additives that may be included in the present invention include lactose, anhydrous lactose, lactose monohydrate, corn starch, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0029] The pharmaceutical composition of the present invention is formulated using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, and surfactants commonly used in the pharmaceutical field. As a solid dosage form for oral administration, tablets, granules, and capsules are particularly preferred, and such solid dosage forms can be prepared according to the conventional method of preparing granules, tablets, and capsules by using at least one excipient in the mixed extract. Additionally, it may include a lubricant such as magnesium stearate and talc, and a disintegrant such as croscarmellose sodium and starch glycolate.

[0030] The preferred dosage of the mixed extract of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the drug, the route of administration, and the duration, but can be appropriately selected by those skilled in the art. Administration may be performed once a day or divided into several doses. The above dosage does not limit the scope of the present invention in any way.

[0031] The present invention will be explained in detail below through examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited to the following examples.

[0032] The present invention relates to a pharmaceutical composition comprising, as an active ingredient, an extract of Pelargonium sidoides, and dihydrocodeine or a pharmaceutically acceptable salt thereof, chlorpheniramine or a pharmaceutically acceptable salt thereof, dl-methyl ephedrine or a pharmaceutically acceptable salt thereof, and ammonium chloride, wherein the composition further comprises a thickening agent, the average particle size of the particles of the composition is less than 210 μm, and the shear rate of the composition is 10 s -1 A composition is provided having a viscosity of 160 to 810 cps as measured.

[0033] In the present invention, pharmaceutically acceptable salts are those that can be prepared by methods conventional in the art, such as, for example, salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium bisulfate, phosphoric acid, nitric acid, carbonic acid, etc.; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin); salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, etc.; salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.; sodium, potassium, etc. It includes metal salts formed by reaction with alkali metals, or salts with ammonium ions, etc.

[0034] The weight ratio of the pharmaceutical composition comprising four types of pharmacologically active substances for the Pelargonium sidoides extract of the present invention may be Pelargonium sidoides extract : dihydrocodeine : dl-methyl ephedrine : chlorpheniramine : ammonium chloride 600~1300 : 4~10 : 17~27 : 0.5~5 : 100~200.

[0035] In the present invention, a thickener refers to a substance that increases viscosity to achieve a desired viscosity. Examples of thickeners include cellulose derivatives such as hydroxypropylcellulose (HPC), hydroxymethylcellulose (HMC), hydroxypropylmethylcellulose (HPMC), methylcellulose polymers, hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), microcrystalline cellulose and sodium carboxymethylcellulose (Avicel RC 591, etc.), carboxymethylene, and carboxymethyl hydroxyethylcellulose; acrylic polymers such as acrylic acid and acrylamide; Examples include xanthan gum, tragacanth, guar gum, gellan gum, agar, pectin, carrageenan, gelatin, bentonite, polyethylene glycol, potassium alginate, and sodium alginate. The content of the thickener is not particularly limited, but may be included in an amount of 0.05 to 30.0 weight% relative to the total weight of the composition.

[0036] In the present invention, the average particle size of the particles of the composition can be obtained by simplifying the particles based on volume and measuring the equivalent circular diameter. The particle size can be measured using a laser diffraction device or the like.

[0037] In one embodiment of the present invention, the average particle size of the particles of the composition is less than 210 μm. If the average particle size is 210 μm or more, phase separation occurs, which reduces phase stability and increases the foreign body sensation when ingested (poor compliance). On the other hand, if the average particle size is too low, it is not efficient because it requires a lot of time and cost to make the particle size smaller.

[0038] In this invention, the viscosity of the composition represents the degree of resistance (viscosity) to deformation of the liquid formulation; high viscosity indicates high stickiness, while low viscosity indicates low stickiness. The viscosity measurement methods defined in the Korean Pharmacopoeia include the capillary viscometer and the rotational viscometer, with the rotational viscometer typically used. A rotational viscometer generally utilizes a cylindrical inner container and a rotating spindle inside it. The rotating spindle is placed in a liquid and rotates at a constant speed, and the resistance generated during this process is measured to calculate the viscosity.

[0039] The Ministry of Food and Drug Safety specifies the importance of verifying the viscosity profiles of oral solutions at various shear rates through its physicochemical equivalence testing guidelines. Unlike rotational viscometers, viscosity profiles at various shear rates can be measured using a rheometer. Viscosity is determined by measuring the stress that a liquid formulation resists when deformation is applied; since the magnitude of the stress resisting deformation changes depending on the rate at which deformation is applied (shear rate), it is important to determine at which deformation rate the viscosity is measured.

[0040] The inventors of the present invention, through theoretical research and various experiments, 10 s -1 It was found that the viscosity measured at a shear rate is related to the phase separation behavior of the composition, the discharge behavior from the pouch, and the filling behavior during packaging, and thus significantly affects phase stability, volume recovery rate, and packaging suitability, and 100 s -1 It was also found that viscosity measured at the shear rate can particularly well represent the filling behavior during packaging of the composition, and thus has a significant impact on packaging suitability.

[0041] In one embodiment of the present invention, the shear rate of the composition is 10 s -1 The viscosity measured at is 160 to 810 cps. Shear rate 10 s -1If the viscosity measured at is less than 160 cps, phase separation may occur, leading to reduced phase stability, and a shear rate of 10 s -1 If the viscosity measured at exceeds 810 cps, ejection from the pouch is poor, which may lead to a poor volume recovery rate. Meanwhile, a shear rate of 10 s -1 If the viscosity measured is less than 160 cps or greater than 810 cps, the packaging suitability may be poor.

[0042] In one embodiment of the present invention, the shear rate of the composition is 100 s -1 The viscosity measured at may be 150 cps or less. Shear rate 100 s -1 If the viscosity measured at exceeds 150 cps, the packaging suitability of the composition may be poor.

[0043] In one embodiment of the present invention, preferably, the shear rate of the composition is 10 s -1 The viscosity measured at may be in the range of 200 to 600 cps.

[0044] In one embodiment of the present invention, preferably, the shear rate of the composition is 100 s -1 The viscosity measured at may be 120 cps or less.

[0045] Meanwhile, the inventors of the present invention have an average particle size and 10 s -1 Noting that viscosity measured at the shear rate affects phase stability and packaging suitability, the interrelationship between them was identified for 10 s -1 It was also found that the ratio of average particle size to viscosity measured at the shear rate affects virtual stability and packaging suitability.

[0046] In one embodiment of the present invention, the shear rate of the composition is 10 s -1 The ratio of average particle size to viscosity measured at may be 1 or less. Shear rate 10 s -1If the ratio of average particle size to viscosity measured in is greater than 1, phase stability or packaging suitability may be poor.

[0047] In one embodiment of the present invention, preferably, the shear rate of the composition is 10 s -1 The ratio of average particle size to viscosity measured in may be 0.6 or less.

[0048] In one embodiment of the present invention, at least one of xanthan gum, guar gum, pectin, sodium carboxymethylcellulose (Na-CMC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), and sodium alginate may be used as a thickening agent. The content of these thickening agents may be 0.05 to 30.0 weight% relative to the total weight of the composition.

[0049] The specific type and content of the thickening agent can be appropriately selected to match the viscosity value measured under the aforementioned conditions to a specific range.

[0050] In one embodiment of the present invention, the composition may further include a preservative.

[0051] In the present invention, a preservative refers to a substance that inhibits the growth of microorganisms in a liquid formulation according to one embodiment. Preferably, the preservative may include one or more of benzoic acids and parabens, or one or more of benzoic acid and sodium benzoate. The content of the preservative is not particularly limited, but may be included in an amount of 0.01 to 0.1 weight% relative to the total weight of the composition.

[0052] In one embodiment of the present invention, the composition may further include a pH adjuster.

[0053] In the present invention, a pH adjuster refers to a substance that changes the acid-alkali balance to reach the desired pH of the composition. Phosphoric acid, sodium phosphate, disodium phosphate, trisodium phosphate, sodium pyrophosphate, citric acid, sodium citrate, tartaric acid, and sodium tartrate may be used as the pH adjuster. Preferably, the pH adjuster may include one or more of citric acid and sodium citrate. The content of the pH adjuster is not particularly limited, but may be included in an amount of 0.01 to 0.2 weight% relative to the total weight of the composition.

[0054] In one embodiment of the present invention, the composition may further include a sweetener.

[0055] In the present invention, a sweetener refers to a substance used to add flavor to a composition. Preferably, the sweetener may include one or more of D-sorbitol, sucralose, acesulfame potassium, stevioside, and sucrose. The content of the sweetener is not particularly limited, but may be included in an amount of 20 to 40 weight percent relative to the total weight of the composition.

[0056] The present invention may be formulated as a liquid preparation for oral administration, which includes suspensions, liquid preparations, emulsions, syrups, etc., and may contain various excipients and additives in a solvent such as purified water.

[0057] In another embodiment according to the present invention, the present invention may provide a composition for the prevention and treatment of respiratory diseases comprising a composition having the improved phase stability and volume recovery rate described above and excellent packaging suitability.

[0058] In the present invention, the term "prevention" refers to any act of suppressing or delaying the onset of the disease through the administration of a composition. Furthermore, in the present invention, the term "treatment" refers to any act of improving or beneficially altering the symptoms of the said disease through the administration of a composition.

[0059] The present invention may also be applied to complex preparations that include Pelargonium sidoides extract as an active ingredient but also include other active ingredients.

[0060] The present invention will be described in more detail below through specific embodiments. These embodiments are intended solely to illustrate the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not to be interpreted as being limited by these embodiments.

[0061] Method for preparing a composition

[0062] The compositions of the following experimental examples were each prepared.

[0063] Active ingredients (Pelargonium sidoides extract, dihydrocodeine tartrate, dl-methyl ephedrine hydrochloride, chlorpheniramine maleate, ammonium chloride) were mixed by stirring in water (purified water) at 80°C or lower, then cooled to 30°C or lower, and a thickening agent, a preservative (sodium benzoate), a pH adjuster, and a sweetener (D-sorbitol) were added. Unless otherwise noted, the remaining examples and comparative examples listed below were prepared using the same manufacturing process as above, and were prepared in 1L units.

[0064] According to the method for preparing the composition described above, the compositions of [Experimental Example 1-1] to [Experimental Example 5-6] were prepared. In [Experimental Example 1-1] to [Experimental Example 5-6], the content of the active ingredients—Pelargonium sidoides extract, dihydrocodeine tartrate, dl-methyl ephedrine hydrochloride, chlorpheniramine maleate, and ammonium chloride—was kept the same.

[0065] [Experimental Examples 1-1] to [Experimental Examples 1-6], [Experimental Examples 2-1] to [Experimental Examples 2-6], [Experimental Examples 3-1] to [Experimental Examples 3-6], [Experimental Examples 4-1] to [Experimental Examples 4-6], and [Experimental Examples 5-1] to [Experimental Examples 5-6] were prepared with average particle sizes of 60 μm, 120 μm, 180 μm, 210 μm, and 240 μm, respectively. The average particle size was measured using the LA-950V2 (model name) of Horiba (manufacturer).

[0066] [Experimental Examples 1-1] through [Experimental Examples 5-6] each controlled the xanthan gum content to a shear rate of 10 s -1 Viscosity (viscosity 1) and shear rate 100 s measured at -1 The viscosity measured in (viscosity 2) was set differently. The viscosity was measured using an Anton Paar rheometer (MCR302e).

[0067] 1. Xanthan gum thickener composition

[0068] Composition of Experimental Example (Unit: %) Ingredient Name Experimental Example 1-1 Experimental Example 1-2 Experimental Example 1-3 Experimental Example 1-4 Experimental Example 1-5 Experimental Example 1-6 Experimental Example 2-1 Experimental Example 2-2 Experimental Example 2-3 Experimental Example 2-4 Active ingredient Pelargonium sidoides extract 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 Dihydrocodeine tartrate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 dl-methyl ephedrine hydrochloride 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 Chlorpheniramine maleate 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 ammonium chloride 1 1 1 1 1 1 1 1 1 1 Thickener Xanthan sword 0.10 0.20 0.25 0.37 0.46 0.55 0.10 0.20 0.25 0.37 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Average particle size (㎛) 60 60 60 60 60 60 120 120 120 120 Viscosity 1 51.5 143.4 205.8 400.7 588.4 811.9 51.5 143.4 205.8 400.7 Viscosity 2 11.8 28.6 38.6 67.2 92.8 122.0 11.8 28.6 38.6 67.2 evaluation Phase stability 0.073 0.026 0.018 0.009 0.006 0.005 0.292 0.105 0.073 0.038 foreign body sensation 1.1 1.2 1.1 1.2 1.1 1.1 1.3 1.4 1.4 1.4 Capacity recovery rate 99.4 99.3 99.1 98.2 95.1 91.1 99.5 99.2 99.0 98.0 Packaging suitability +++ + Good Good Good + +++ + Good Good

[0070] Composition of Experimental Example (Unit: %) Ingredient Name Experimental Example 2-5 Experimental Example 2-6 Experimental Example 3-1 Experimental Example 3-2 Experimental Example 3-3 Experimental Example 3-4 Experimental Example 3-5 Experimental Example 3-6 Experimental Example 4-1 Experimental Example 4-2 Active ingredient Pelargonium sidoides extract 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 Dihydrocodeine tartrate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 dl-methyl ephedrine hydrochloride 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 Chlorpheniramine maleate 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 ammonium chloride 1 1 1 1 1 1 1 1 1 1 Thickener Xanthan sword 0.46 0.55 0.10 0.20 0.25 0.37 0.46 0.55 0.10 0.20 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Average particle size (㎛) 120 120 180 180 180 180 180 180 210 210 Viscosity 1 588.4 811.9 51.5 143.4 205.8 400.7 588.4 811.9 51.5 143.4 Viscosity 2 92.8 122.0 11.8 28.6 38.6 67.2 92.8 122.0 11.8 28.6 evaluation Phase stability 0.026 0.019 0.657 0.236 0.095 0.085 0.058 0.042 0.895 0.322 foreign body sensation 1.5 1.3 2.3 2.1 1.9 1.7 1.8 1.7 4.2 4.1 Capacity recovery rate 95 89.5 99.3 99.1 99.0 98.4 95.3 90.3 99.0 98.5 Packaging suitability Good + +++ + Good Good Good + +++ +

[0072] Composition of Experimental Example (Unit: %) Ingredient Name Experimental Example 4-3 Experimental Example 4-4 Experimental Example 4-5 Experimental Example 4-6 Experimental Example 5-1 Experimental Example 5-2 Experimental Example 5-3 Experimental Example 5-4 Experimental Example 5-5 Experimental Example 5-6 Active ingredient Pelargonium sidoides extract 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 6.178 Dihydrocodeine tartrate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 dl-methyl ephedrine hydrochloride 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 0.131 Chlorpheniramine maleate 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.015 ammonium chloride 1 1 1 1 1 1 1 1 1 1 Thickener Xanthan sword 0.25 0.37 0.46 0.55 0.10 0.20 0.25 0.37 0.46 0.55 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Average particle size (㎛) 210 210 210 210 240 240 240 240 240 240 Viscosity 1 205.8 400.7 588.4 811.9 51.5 143.4 205.8 400.7 588.4 811.9 Viscosity 2 38.6 67.2 92.8 122.0 11.8 28.6 38.6 67.2 92.8 122.0 evaluation Phase stability 0.224 0.115 0.079 0.057 0.989 0.420 0.293 0.151 0.103 0.075 foreign body sensation 4.1 4.3 4.2 4.1 4.8 4.7 4.8 4.5 4.3 4.2 Capacity recovery rate 98.3 97.8 95.1 89.8 99.2 99.0 98.8 98.2 95.5 90.8 Packaging suitability Good Good Good + +++ + Good Good Good +

[0073] For [Experimental Example 1-1] to [Experimental Example 5-6] obtained in this manner, phase stability, foreign matter sensation, volume recovery rate, and packaging suitability were measured or evaluated in the following way.

[0074] Phase stability

[0075] 1) Criterion: Instability index less than 0.1

[0076] 2) Test conditions: After placing the sample into a 2 mm type cell, the instability index is measured by operating at 4000 rpm at 25 ℃ for 9 hours.

[0077] 3) The instability index is a numerical value indicating the degree of phase change, and the more severe the phase separation, the closer the value is to the maximum of 1. It was confirmed that when the content of semi-finished products with a value of 0.1 (10%) or higher, indicating a phase change, is evaluated, it may be non-compliant with the content standard of 90.0 to 110.0%. The test conditions of 4000 rpm and 9 hours are accelerated conditions designed to correspond to the product's shelf life of 2 years.

[0078] foreign body sensation

[0079] 1) Criteria: 4.0 or higher when evaluated on a 5-point scale

[0080] 2) If the particle size of the liquid is larger than a certain size, it may cause discomfort due to a foreign body sensation when ingested. The degree of discomfort caused by the foreign body sensation when ingesting the product was evaluated using a 5-point scale on 30 randomly selected subjects.

[0081] (5 points: Very uncomfortable, 4 points: Uncomfortable, 3 points: Average, 2 points: Not uncomfortable, 1 point: Not uncomfortable at all)

[0082] Dose recovery rate (dosage accuracy)

[0083] 1) Criteria: Volume recovery rate of 95% or higher

[0084] 2) Liquid formulations packaged in pouches are taken by squeezing them by hand; however, if the viscosity is too high, the contents of the pouch do not come out easily, making it difficult for the patient to take the correct dosage. To evaluate this, three randomly selected individuals squeezed out the contents of 5 pouches each, for a total of 15 pouches, and measured the amount obtained to calculate the dosage recovery rate. The content evaluation criteria for the composition is 90 to 110% (0.9A to 1.1A / mL, where A is the indicated amount), and the dosage and filling amount are set to 20 mL. Based on the lower limit content value of 90%, taking the entire 20 mL (0.9A / mL x 20 mL = 18A or more) can produce an effective effect. As a result of evaluating the actual content of the compositions in several batches, the content was 95 to 105%, and a standard was established based on the fact that the dose recovery rate must be 19 mL or more (95% or more) based on the minimum content of 95% in order to take the active ingredient corresponding to 18A (≈0.95A / mL x 19 mL) or more.

[0085] Packaging suitability (whether packaging is defective)

[0086] 1) Criteria: Occurrence of 3 phenomena (① Liquid leakage after filling ② Poor bonding ③ Underweight during filling)

[0087] 2) Pouch packaging filling is performed by repeating the processes of vertical bonding, horizontal bonding, content injection, horizontal cutting, and packaging material supply using a roll-type film. The content injection process is carried out through a filling nozzle; however, during the injection, the contents may splash up and adhere to the top of the pouch, and after the correct amount is injected, contents accumulating at the tip of the filling nozzle may fall and adhere to the top. If contents adhere to the top of the pouch in this manner, proper heat conduction does not occur during horizontal bonding, resulting in bonding defects. Consequently, leakage may occur, causing the weight to fall below the standard. Furthermore, if the contents exiting through the filling nozzle do not separate and instead stretch out, adhering to the top of the pouch, bonding defects may occur, leading to leakage and a weight that falls below the standard. Additionally, due to high viscosity, high pressure is applied to the filling machine, preventing the fill volume from being filled, which may result in the weight falling below the standard. When filling 20 pouches using a fluid pump in the laboratory, the evaluation is based on the number of pouches that do not meet the weight standard: 3 pouches or more: +++, 2 pouches: ++, 1 pouch: +, 0 pouches: -(Good).

[0088] According to [Table 1] to [Table 3] above, samples with average particle sizes of 210 μm and 240 μm showed poor phase stability, with instability indices mostly being 0.1 or higher (Experimental Examples 4-1 to 4-6, Experimental Examples 5-1 to 5-6). Samples with average particle sizes of 210 μm and 240 μm also showed a high foreign body sensation (Experimental Examples 4-1 to 4-6, Experimental Examples 5-1 to 5-6).

[0089] Viscosity of composition 1 (shear rate 10 s -1Samples with a viscosity (measured at) of less than 160 cps showed phase separation and low phase stability (Experimental Example 2-1, Experimental Example 2-2, Experimental Example 3-1, Experimental Example 3-2, Experimental Example 4-1, Experimental Example 4-2, Experimental Example 5-1, Experimental Example 5-2), and samples with a viscosity of more than 810 cps showed poor discharge behavior from the pouch and low volume recovery rate (Experimental Example 1-6, Experimental Example 2-6, Experimental Example 3-6, Experimental Example 4-6, Experimental Example 5-6). Some samples with a viscosity of less than 160 cps or greater than 810 cps had poor packaging suitability (Experimental Example 1-1, Experimental Example 1-2, Experimental Example 1-6, Experimental Example 2-1, Experimental Example 2-2, Experimental Example 2-6, Experimental Example 3-1, Experimental Example 3-2, Experimental Example 3-6, Experimental Example 4-1, Experimental Example 4-2, Experimental Example 4-6, Experimental Example 5-1, Experimental Example 5-2, Experimental Example 5-6).

[0090] Viscosity of composition 2 (shear rate 100 s -1 The viscosity measured in was found to be 150 cps or less for all of them.

[0091] Meanwhile, samples in which the ratio of average particle size to viscosity 1 of the composition was greater than 1 were found to have poor phase stability or poor packaging suitability (Experimental Example 1-1, Experimental Example 2-1, Experimental Example 3-1, Experimental Example 3-2, Experimental Example 4-1, Experimental Example 4-2, Experimental Example 4-3, Experimental Example 5-1, Experimental Example 5-2, Experimental Example 5-3).

[0093] 2. Na-CMC Thickener Composition

[0094] Composition of Experimental Example (Unit: %) Ingredient Name Experimental Example 6-1 Experimental Example 6-2 Experimental Example 6-3 Experimental Example 6-4 Experimental Example 6-5 Experimental Example 6-6 Active ingredient Pelargonium sidoides extract 6.178 6.178 6.178 6.178 6.178 6.178 Dihydrocodeine tartrate 0.05 0.05 0.05 0.05 0.05 0.05 dl-methyl ephedrine hydrochloride 0.131 0.131 0.131 0.131 0.131 0.131 Chlorpheniramine maleate 0.015 0.015 0.015 0.015 0.015 0.015 ammonium chloride 1 1 1 1 1 1 Thickener Na-CMC 0.20 0.45 0.55 0.75 0.85 0.95 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Average particle size (㎛) 120 120 120 120 120 120 Viscosity 1 49.7 150.4 214.7 428.1 592.4 843.6 Viscosity 2 32.1 77.3 102.1 174.8 224.9 296.0 evaluation Phase stability 0.291 0.104 0.072 0.038 0.025 0.019 foreign body sensation 1.4 1.4 1.4 1.5 1.5 1.3 Capacity recovery rate 99.4 99.3 99.0 98.5 95.2 89.5 Packaging suitability Good Good Good + + +

[0095] According to the method of preparing the composition described above, [Experimental Example 6-1] to [Experimental Example 6-6] were prepared as shown in [Table 4], and phase stability, foreign matter sensation, volume recovery rate, and packaging suitability were measured or evaluated.

[0096] According to [Table 4] above, samples with a viscosity 1 of the composition of less than 160 cps exhibited phase separation and low phase stability (Experimental Examples 6-1 and 6-2), while samples with a viscosity 1 of more than 810 cps showed poor discharge behavior from the pouch, resulting in a low volume recovery rate and poor packaging suitability (Experimental Example 6-6). Samples with a viscosity 2 of the composition of more than 150 cps showed somewhat poor packaging suitability during the packaging process (Experimental Examples 6-4, 6-5, and 6-6).

[0097] Meanwhile, samples in which the ratio of average particle size to viscosity of the composition was greater than 1 were found to have poor phase stability (Experimental Example 6-1).

[0099] 3. HPMC Thickener Composition

[0100] Composition of Experimental Example (Unit: %) Ingredient Name Experimental Example 7-1 Experimental Example 7-2 Experimental Example 7-3 Experimental Example 7-4 Experimental Example 7-5 Experimental Example 7-6 Active ingredient Pelargonium sidoides extract 6.178 6.178 6.178 6.178 6.178 6.178 Dihydrocodeine tartrate 0.05 0.05 0.05 0.05 0.05 0.05 dl-methyl ephedrine hydrochloride 0.131 0.131 0.131 0.131 0.131 0.131 Chlorpheniramine maleate 0.015 0.015 0.015 0.015 0.015 0.015 ammonium chloride 1 1 1 1 1 1 Thickener HPMC 0.05 0.30 0.38 0.48 0.52 0.58 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Average particle size (㎛) 120 120 120 120 120 120 Viscosity 1 55.2 140.3 211.4 431.3 585.1 836.9 Viscosity 2 13.2 66.6 96.2 155.1 196.6 247.8 evaluation Phase stability 0.162 0.105 0.071 0.040 0.027 0.018 foreign body sensation 1.3 1.3 1.4 1.4 1.5 1.3 Capacity recovery rate 99.5 99.1 99.1 98.3 95.1 89.5 Packaging suitability +++ Good Good + + +

[0101] According to the method of preparing the composition described above, [Experimental Example 7-1] to [Experimental Example 7-6] were prepared as shown in [Table 5], and phase stability, foreign matter sensation, volume recovery rate, and packaging suitability were measured or evaluated.

[0102] According to [Table 5] above, samples with a viscosity of less than 160 cps of the composition exhibited phase separation and low phase stability (Experimental Example 7-1, Experimental Example 7-2), samples with a viscosity of more than 810 cps exhibited poor discharge behavior from the pouch and low volume recovery rate (Experimental Example 7-6), and samples with a viscosity of less than 160 cps or more than 810 cps also showed poor packaging suitability during the packaging process (Experimental Example 7-1, 7-6).

[0103] Samples with a viscosity of 2 of the composition exceeding 150 cps were found to have somewhat poor packaging suitability (Experimental Examples 7-4, 7-5, and 7-6).

[0104] Meanwhile, samples in which the ratio of average particle size to viscosity of the composition was greater than 1 were found to have poor phase stability and packaging suitability (Experimental Example 7-1).

[0106] 4. HEC Thickener Composition

[0107] Composition of Experimental Example (Unit: %) Ingredient Name Experimental Example 8-1 Experimental Example 8-2 Experimental Example 8-3 Experimental Example 8-4 Experimental Example 8-5 Experimental Example 8-6 Active ingredient Pelargonium sidoides extract 6.178 6.178 6.178 6.178 6.178 6.178 Dihydrocodeine tartrate 0.05 0.05 0.05 0.05 0.05 0.05 dl-methyl ephedrine hydrochloride 0.131 0.131 0.131 0.131 0.131 0.131 Chlorpheniramine maleate 0.015 0.015 0.015 0.015 0.015 0.015 ammonium chloride 1 1 1 1 1 1 Thickener HEC 0.50 0.70 0.80 1.00 1.10 1.20 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Average particle size (㎛) 120 120 120 120 120 120 Viscosity 1 55.7 150.0 232.9 402.8 583.7 827.4 Viscosity 2 37.6 79.8 111.6 170.4 227.4 298.4 evaluation Phase stability 0.270 0.100 0.065 0.037 0.026 0.018 foreign body sensation 1.4 1.3 1.4 1.4 1.5 1.3 Capacity recovery rate 99.3 99.4 99.1 98.3 95.1 89.1 Packaging suitability Good Good Good + + +

[0108] According to the method of preparing the composition described above, [Experimental Example 8-1] to [Experimental Example 8-6] were prepared as shown in [Table 6], and phase stability, foreign matter sensation, volume recovery rate, and packaging suitability were measured or evaluated.

[0109] According to [Table 6] above, samples with a viscosity of less than 160 cps of the composition exhibited phase separation and low phase stability (Experimental Example 8-1, Experimental Example 8-2), samples with a viscosity of more than 810 cps exhibited poor discharge behavior from the pouch and low volume recovery rate (Experimental Example 8-6), and samples with a viscosity of more than 810 cps also had poor packaging suitability (Experimental Example 8-6).

[0110] Samples with a viscosity of 2 of the composition exceeding 150 cps had somewhat poor packaging suitability (Experimental Examples 8-4, 8-5, and 8-6).

[0111] Meanwhile, samples in which the ratio of average particle size to viscosity of the composition was greater than 1 were found to have poor phase stability (Experimental Example 8-1).

[0113] 5. Sodium alginate thickener composition

[0114] Composition of Experimental Example (Unit: %) Ingredient Name Experimental Example 9-1 Experimental Example 9-2 Experimental Example 9-3 Experimental Example 9-4 Experimental Example 9-5 Experimental Example 9-6 Active ingredient Pelargonium sidoides extract 6.178 6.178 6.178 6.178 6.178 6.178 Dihydrocodeine tartrate 0.05 0.05 0.05 0.05 0.05 0.05 dl-methyl ephedrine hydrochloride 0.131 0.131 0.131 0.131 0.131 0.131 Chlorpheniramine maleate 0.015 0.015 0.015 0.015 0.015 0.015 ammonium chloride 1 1 1 1 1 1 Thickener Sodium alginate 5.0 7.3 7.8 9.0 9.6 10.3 purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Average particle size (㎛) 120 120 120 120 120 120 Viscosity 1 61.5 144.1 210.1 438.6 590.0 810.7 Viscosity 2 60.8 138.4 195.2 389.8 517.9 704.2 evaluation Phase stability 0.245 0.104 0.072 0.034 0.026 0.019 foreign body sensation 1.4 1.4 1.3 1.3 1.5 1.3 Capacity recovery rate 99.4 99.3 99.2 98.5 95.7 89.1 Packaging suitability Good Good + + +++ +++

[0115] According to the method of preparing the composition described above, [Experimental Example 9-1] to [Experimental Example 9-6] were prepared as shown in [Table 7], and phase stability, foreign matter sensation, volume recovery rate, and packaging suitability were measured or evaluated.

[0116] According to [Table 7] above, samples with a viscosity of less than 160 cps of the composition exhibited phase separation and low phase stability (Experimental Example 9-1, Experimental Example 9-2), samples with a viscosity of more than 810 cps exhibited poor discharge behavior from the pouch and low volume recovery rate (Experimental Example 9-6), and samples with a viscosity of more than 810 cps also showed poor packaging suitability during the packaging process (Experimental Example 9-6).

[0117] Samples with a viscosity of 2 of the composition exceeding 150 cps had somewhat poor packaging suitability (Experimental Examples 9-3, 9-4, 9-5, and 9-6).

[0118] Meanwhile, samples in which the ratio of average particle size to viscosity of the composition was greater than 1 were found to have poor phase stability (Experimental Example 9-1).

[0120] Optimal embodiments have been disclosed in the specification as described above. Specific terms have been used herein, but they are used only for the purpose of describing the invention and are not intended to limit the meaning or the scope of the invention as described in the claims. Therefore, those skilled in the art will understand that various modifications and equivalent alternative embodiments are possible therefrom. Accordingly, the true technical scope of protection of the invention should be determined by the technical spirit of the appended claims.

Claims

Claim 1 A pharmaceutical composition comprising, as an active ingredient, Pelargonium sidoides extract; and dihydrocodeine or a pharmaceutically acceptable salt thereof, chlorpheniramine or a pharmaceutically acceptable salt thereof, dl-methyl ephedrine or a pharmaceutically acceptable salt thereof, and ammonium chloride, wherein the composition further comprises a thickening agent, the average particle size of the particles of the composition is less than 210 μm, and the shear rate of the composition is 10 s -1 A composition having a viscosity of 160 to 810 cps as measured. Claim 2 In claim 1, the shear rate of the composition is 100 s -1 A composition characterized by a viscosity of 150 cps or less as measured. Claim 3 In claim 1, the shear rate of the composition is 10 s -1 A composition characterized by the ratio of the average particle size to the viscosity measured in being 1 or less. Claim 4 A composition according to claim 1, characterized in that the thickening agent comprises one or more of xanthan gum, guar gum, pectin, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, and sodium alginate. Claim 5 In claim 1, the shear rate of the composition is 10 s -1 A composition characterized by a viscosity measured in the range of 200 to 600 cps. Claim 6 In claim 1, the shear rate of the composition is 100 s -1 A composition characterized by a viscosity of 120 cps or less as measured. Claim 7 In claim 1, the shear rate of the composition is 10 s -1 A composition characterized by the ratio of the average particle size to the viscosity measured in being 0.6 or less. Claim 8 A composition according to claim 1, characterized in that the composition further comprises a preservative. Claim 9 A composition according to claim 1, characterized in that the composition further comprises a pH adjuster. Claim 10 A composition according to claim 1, characterized in that the composition further comprises a sweetener. Claim 11 A composition for the prevention and treatment of respiratory diseases comprising the composition of claim 1.