WO2021080185A1 - Préparation de petite taille à libération prolongée destinée à être administrée par voie orale contenant de l'alfoscérate de choline - Google Patents

Préparation de petite taille à libération prolongée destinée à être administrée par voie orale contenant de l'alfoscérate de choline Download PDF

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WO2021080185A1
WO2021080185A1 PCT/KR2020/012472 KR2020012472W WO2021080185A1 WO 2021080185 A1 WO2021080185 A1 WO 2021080185A1 KR 2020012472 W KR2020012472 W KR 2020012472W WO 2021080185 A1 WO2021080185 A1 WO 2021080185A1
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pharmaceutical composition
release
weight
sustained
choline alfoscerate
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PCT/KR2020/012472
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English (en)
Korean (ko)
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김성엽
송희용
김병진
최연웅
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한국유나이티드제약 주식회사
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Publication of WO2021080185A1 publication Critical patent/WO2021080185A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • the present invention relates to a small-sized oral pharmaceutical preparation containing choline alfoscerate, and more specifically, to a sustained-release small-sized oral dosage formulation having excellent dosage convenience and bioavailability due to the small size of the dosage form while the active ingredient is slowly released over a long period of time. .
  • An aging phenomenon is appearing with an extension of life span around the world, and this phenomenon is occurring more remarkably especially in advanced countries.
  • the global aging phenomenon the number of dementia patients is gradually increasing compared to the past, and accordingly, interest in the development of dementia treatments is also increasing.
  • Alzheimer's disease is the most common cause of dementia, which accounts for about 60-70% of all dementia.
  • a decrease in the activity of acetylcholine is a major phenomenon, which leads to a decrease in cholinergic neurons and a decrease in cholinergic function of the brain, leading to a decrease in cognitive function.
  • abnormal proteins such as amyloid plaque and neurofibrillary tangle accumulate in the brain, destroying brain cells and reducing brain tissue, resulting in loss of brain function.
  • decreased activity is associated with the formation of amyloid plates.
  • Choline alfoscerate is a cholinergic precursor and has a high bioavailability of 88%, and in particular, it passes through the blood brain barrier by 45% and has a significant amount of its medicinal effect in the brain. In the body, choline and glycerophosphate are separated and acted. Choline is used as a precursor for synthesizing acetylcholine, which normalizes the neurotransmitter function reduced by brain nerve damage. It is metabolized to normalize the function of damaged nerve cells.
  • the present invention provides a pharmaceutical composition containing choline alfoscerate as an active ingredient as a dementia treatment agent.
  • Choline alfoscerate is a compound also called L- ⁇ -glyceryl phosphoryl choline (L-GPC), and has the following structure.
  • a pharmaceutical formulation containing choline alfoscerate is a formulation that is taken three times a day, and soft capsules and tablet form formulations are commercially available.
  • the amount of active ingredient administered is 400 mg of choline alfoscerate at a time, and its size is large (long axis: 16.1 mm, short axis: 8.5 mm, thickness: 8.5 mm, reference drug: gliatyrin soft) Capsules) are taken three times a day, so there are insufficient parts to satisfy patients' adherence.
  • Patent Document 1 Korean Patent Laid-Open Patent No. 10-2013-0010044 uses choline alfoscerate as an active ingredient and uses insoluble bases such as hypromellose and ethyl cellulose. And it proposes a sustained-release tablet prepared in a form in which particles coated with a sustained-release coating are prepared by spraying a polymer as a coating solution on choline alfoscerate powder using a fluidized bed coater, and then the particles are tableted together with an additional excipient.
  • the formulation of Patent Document 1 has a problem of low economic efficiency due to a low process yield, and because the size of the tablet is large, the ease of administration is also a problem considering that most of the patients taking choline alfoscerate are elderly people.
  • Patent Document 2 (Korean Patent Publication No. 10-2015-0066937) is a formulation that uses calcium silicate mainly to reduce the amount of excipients used as adsorbents, thereby simplifying the manufacturing method and making the tablet size relatively small. Has been provided. Therefore, compared to the formulation of Patent Document 1, there is an advantage in terms of medication compliance.
  • the process of Patent Document 2 is to block moisture in the air after the production of uncoated tablets. The process is complicated, and the tabletting ability of calcium silicate, which is essential as an adsorbent, is very poor, and there is a high possibility of tableting failure. . Therefore, there is a high possibility that the individual variation of each manufactured tablet becomes large, and thus, the triple coating state also has a high defect rate and thus the process efficiency is degraded.
  • Patent Document 3 (Korean Patent No. 10-1796628) is a film-coated tablet coated with a coating solution consisting of hydroxypropylmethylcellulose and polyvinyl alcohol on uncoated tablets obtained by adsorbing choline alfoscerate on magnesium metasilicate aluminate. .
  • a coating solution consisting of hydroxypropylmethylcellulose and polyvinyl alcohol
  • the content of magnesium metasilicate aluminate used to adsorb choline alfoscerate is 62.5% compared to the active ingredient, the size of the tablet is inevitably increased. There is a problem of falling.
  • the individual size of the formulation proposed in the prior art is greatly reduced, thereby including the content of active ingredients equivalent to the conventional choline alfoscerate formulation taken three times a day. It is an object of the present invention to provide a pharmaceutical composition having excellent medication convenience, which is composed of individual formulations of a size that is not burdensome to take.
  • the pharmacological effect appears quickly with rapid release at the beginning, but the effect lasts for 24 hours, which is equivalent to the conventional choline alfoscerate formulation, which was taken three times a day just by taking once a day. It is an object to provide a pharmaceutical composition having an effect.
  • the pharmaceutical composition of the present invention is characterized in that it contains choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, and is made of a seamless formulation that does not include a capsule coating layer.
  • the pharmaceutical composition may have excellent moldability and stability by additionally including a gelling agent and a curing agent if necessary.
  • the gelling agent may be one or a mixture of two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch.
  • other pharmaceutically acceptable gelling agents may be used.
  • the applicant has confirmed the suitability of the formulation through an experiment, and if an inappropriate gelling agent is used, gelation is not possible in a short time during the molding process of seamless soft capsules. As it does not occur, it is not possible to maintain a spherical and uniform form of the formulation.
  • the pharmaceutical composition of the present invention is prepared in a small spherical formulation, packaged in a pouch containing a plurality of formulations, and administered by oral administration of one packet once a day. Therefore, since a plurality of formulations are simultaneously administered by oral administration, it is important to maintain the spherical shape as shown in the photograph of FIG. 2 so that administration can be performed without discomfort in the neck.
  • the gelling agent may be included in 50 to 80% by weight, more specifically 55 to 70% by weight, 65 to 75% by weight, and most preferably 60 to 70% by weight, based on the total weight of the active ingredient.
  • the pharmaceutical composition of the present invention is mixed with the gelling agent with choline alfoscerate and purified water in the manufacturing step, the weight of the gelling agent is at least at least choline alfoscerate and purified water. It is most preferably a range included in a weight ratio of 1:6 to 1:7 based on the combined weight. If the weight of the gelling agent is out of the range described above, the formulation may collapse during molding, or it is difficult to maintain a stable spherical shape.
  • the curing agent may be selectively used in one or two or more types from the group consisting of cellulose derivatives, sugars, and silicon-based compounds. More specifically, the curing agent is one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, talc, sorbitol, mannitol, colloidal silicon dioxide, magnesium aluminate silicate, calcium silicate, microcrystalline cellulose, light anhydrous silicic acid or It may be a mixture of two or more, most preferably colloidal silicon dioxide.
  • the pharmaceutical composition of the present invention may not contain a plasticizer.
  • plasticizers are included to impart flexibility in soft capsule formulations containing gelatin, but the pharmaceutical composition of the present invention is a seamless formulation in which choline alfoscerate and gelatin components are mixed, and the active ingredient is in addition to the expression of pharmacological effects. It can serve as a function that gives flexibility. Therefore, the pharmaceutical composition of the present invention can secure the flexibility suitable for formulation processing without including a small amount or no plasticizer at all.
  • the content of the active ingredient in the pharmaceutical composition of the present invention is preferably 40 to 60% by weight based on the total weight of the pharmaceutical composition. Since the active ingredient exhibits a pharmacological effect and acts as a plasticizer at the same time, if it is included in an excessive amount outside the above range, stability during manufacture may be poor, and it may not be molded into a desired shape, and sustained-release to show sustained-release properties. Base coating can be difficult. In addition, the blood concentration can rise rapidly, and side effects can occur. On the other hand, if included below the above range, the formulation may be disintegrated during manufacture due to poor processability, and the expression of pharmacological effects may be delayed.
  • the curing agent is preferably 10 to 25% by weight based on the total weight of the pharmaceutical composition, and more specifically, 10 to 20% by weight, 15 to 25% by weight may be included. Most preferably, it may contain 10 to 15% by weight.
  • the content of the curing agent is less than 10% by weight, the formulation flexibility is too high, so that the molding is difficult and stability is poor, and when a plurality of pharmaceutical compositions are stored together, a problem of adhering to each other may occur.
  • the content of the curing agent exceeds 25% by weight, defects in which the formulation is broken or cracked during molding may occur.
  • the pharmaceutical composition of the present invention may be coated with a moisture barrier material containing a water-soluble polymer, and thus, formulation stability can be maintained for a long period of time even when exposed to outside air containing moisture.
  • a moisture barrier agent one or a mixture of two or more selected from the group consisting of methacrylic acid, ethyl acrylate copolymer, polyvinyl alcohol, and hydroxypropylmethylcellulose may be used.
  • the content of the moisture barrier agent may be 3 to 10% by weight based on the total weight of the pharmaceutical composition, more specifically 4 to 7% by weight, 6 to 9% by weight, most preferably 5 to 8% by weight. I can.
  • the total weight of the pharmaceutical composition of the present invention may be prepared as 20 to 60 mg, more preferably 30 to 50 mg of soft capsules.
  • the present invention provides a pharmaceutical composition further comprising as an active ingredient donepezil or a pharmaceutically acceptable salt thereof, which is known to exhibit a synergistic effect when administered in combination with choline alfoscerate. More specifically, by including donepezil hydrochloride in a capsule together with choline alfoscerate, a more excellent pharmacological effect can be expected.
  • the content of donepezil or a pharmaceutically acceptable salt thereof may be 1 to 7% by weight, more preferably 2 to 6% by weight, based on the total weight of choline alfoscerate.
  • the pharmaceutical composition of the present invention further provides a formulation in which a sustained-release coating layer containing a sustained-release base agent is formed on a soft capsule in order to express a sufficient effect by taking one packet once a day.
  • the sustained-release base may include a water-soluble polymer and a water-insoluble polymer.
  • the water-soluble polymer may be one or two or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyvinyl alcohol, polyethylene glycol, and the like, and the water-insoluble polymer is polyvinylacetic acid, ethyl One or two or more selected from the group consisting of cellulose and ethyl methacrylate may be used.
  • the content ratio of the water-soluble polymer and the water-insoluble polymer of the sustained-release base may be 1:2 to 1:5 by weight. More specifically, the content ratio of the water-soluble polymer and the water-insoluble polymer may be 1:3 to 1:5, 1:2 to 1:4, and most preferably 1:3 to 1:4.
  • the weight of the sustained-release coating layer may be 5 to 40% by weight based on the total weight of the pharmaceutical composition excluding the sustained-release coating layer, more specifically 10 to 25% by weight, 20 to 35% by weight, most preferably It may be 15 to 30% by weight.
  • the weight of the sustained-release coating layer is less than 5% by weight, the sustained-release property does not appear, and when the weight of the sustained-release coating layer exceeds 40% by weight, the dissolution of the active ingredient may be delayed and the pharmacological effect may not be sufficiently expressed.
  • the pharmaceutical composition of the present invention further comprises an anti-adhesion agent of 40 to 60% by weight, more specifically 40 to 55% by weight, 45 to 60% by weight, most preferably 45 to 55% by weight, based on the total weight of the sustained-release coating layer. can do.
  • the pharmaceutical preparation containing the pharmaceutical composition of the present invention is one package as a dosage unit, and contains a pharmaceutical composition in a plurality of soft capsule formulations in one package.
  • the anti-adhesion agent serves to prevent the individual soft capsules contained in one packet from sticking to each other. At this time, the anti-adhesion agent may be preferably talc.
  • the pharmaceutical formulation containing the pharmaceutical composition of the present invention is 1 package as 1 dosage unit, and in 1 package, based on the total weight of the formulation, 20 to 40% by weight of the pharmaceutical composition formulation without the sustained-release agent coating, and the sustained-release agent It may contain 60 to 80% by weight of the coated pharmaceutical composition.
  • the residence time in the gastrointestinal tract appears to be 18 to 24 hours, and when passing through the gastrointestinal tract, 20 to 50% of choline alfoscerate or its salt is eluted from the stomach, and 50 to 50 in the intestine. 80% of choline alfoscerate or salt thereof is eluted. Specifically, it is characterized by satisfying the following dissolution profile in pH 4.0, 6.8, 1.2, and water eluate according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method.
  • One single-layer soft capsule for oral administration consisting of a plurality of immediate-release preparations and a plurality of sustained-release preparations prepared according to the present invention is capable of controlling the dissolution rate of the drug using a pharmaceutically acceptable sustained-release base, When ingested, it maintains a constant blood concentration through rapid effect and continuous release of the active ingredient for a considerable period of time. While reducing the number of doses compared to conventional formulations, the size of individual formulations is reduced to improve ease of administration, so long-term administration patients can be expected to improve the therapeutic effect compared to conventional formulations.
  • FIG. 1 is a schematic diagram showing a comparison of a conventional seamless soft capsule divided into two layers of a capsule base and an inner liquid, and a seamless soft capsule of the present invention prepared by mixing a gelling agent and an inner liquid without distinction of layers.
  • FIG. 2 is a photograph showing properties before storage under accelerated conditions of a temperature of 40 ⁇ 2°C and a relative humidity of 75 ⁇ 5% for Example 1, Example 5, Control Drug 1, and Control Drug 2.
  • FIG. Example 1, Example 5, control drug 1, control drug 2 in clockwise direction
  • control drug 1 is a change in properties after storage for 3 days in an accelerated condition of a temperature of 40 ⁇ 2°C and a relative humidity of 75 ⁇ 5% for the formulations prepared in Examples 1 to 5, control drug 1, and control drug 2 Is a photograph showing (Clockwise Example 1, Example 5, control drug 1, control drug 2)
  • Figure 4 shows the results of the dissolution test in water for the formulations prepared in Examples 6 to 10.
  • FIG. 5 shows water obtained by using 20 capsules of Example 4 (400 mg as choline alfoscerate) and 40 capsules of Example 9 (800 mg as choline alfoscerate) as a unit for the formulations prepared in Examples 4 and 9 It shows the results of the dissolution test at.
  • Example 6 is a pH of Example 4 20 capsules (400 mg as choline alfoscerate) and 40 capsules of Example 9 (800 mg as choline alfoscerate) as one unit for the formulations prepared in Examples 4 and 9 It shows the results of the dissolution test in 1.2.
  • FIG. 7 shows 20 capsules of the formulation of Example 4 (400 mg as choline alfoscerate) and 40 capsules of the formulation of Example 9 (800 mg as choline alfoscerate) as a unit of the formulations prepared in Examples 4 and 9 It shows the results of the dissolution test conducted at pH 4.0.
  • FIG. 8 shows the formulations prepared in Example 4 and Example 9, in which 20 capsules of Example 4 (400 mg as choline alfoscerate) and 40 capsules of Example 9 formulation (800 mg as choline alfoscerate) were carried out as one unit. It shows the results of the dissolution test at pH 6.8.
  • choline alfoscerate soft capsules or tablets are released in a dosage form taken 2-3 times a day, and through many clinical studies, the efficacy of oral administration of 1200mg per day has been proved. Due to the nature of the drug, choline alfoscerate has a bioavailability close to 90%, so its absorption rate is very excellent, but when administered orally, the maximum concentration in the blood occurs in 1.5 hours and the duration of the drug is about 6 hours, showing a relatively short-term drug. It appears that it is necessary to develop a new formulation using sustained-release technology in order to secure continuous medicinal effects.
  • the choline alfoscerate oral administration formulation according to the present invention is based on a solid soft capsule containing choline alfoscerate or a salt thereof, a hardener, and a gelling agent in one package, and is generally in the corresponding capsule. It includes a number of immediate-release soft capsules coated with a film coating and sustained-release soft capsules additionally coated with a sustained-release agent coating.
  • a plasticizer may be optionally added to the coating base or formulation as needed, but the present invention has the advantage of securing excellent flexibility without a plasticizer.
  • the total weight of the pharmaceutical composition formulation for one unit before coating is 2500 mg or less, and the weight after coating is 3000 mg or less, and the weight of the individual formulation is 50 mg or less in the case of an immediate-release formulation, and In this case, a formulation of 60 mg or less is provided.
  • the size of a small capsule when taking it so there is no difficulty swallowing, it is excellent in dosage convenience, it is possible to increase the medication adherence due to the decrease in the number of doses due to taking one packet once a day, and the manufacturing process is simple, so it is economical.
  • choline alfoscerate formulations can be prepared in tablet formulations and soft capsule formulations. According to the characteristics of the active ingredient and the excipients used together, it is as follows to determine which formulation is more suitable for minimizing the total weight of the formulation and achieving miniaturization of individual formulations.
  • a method of manufacturing by molding into a soft capsule can be considered.
  • Representative manufacturing methods include a rotary molding method and a seamless molding method.
  • the rotary method is a method of injecting an active ingredient liquid into the middle of both rotary rollers, rotating the rollers and bonding the film to form, and the seamless molding method is also referred to as the dripping method or the Globex method. It is a method of forming a soft material with the difference in surface tension between the two solutions by spraying the liquid and the internal active ingredient at the same time.
  • the seamless molding method has a thinner moldable minimum film thickness compared to rotary molding in terms of pharmaceuticals, and the capsule size can be easily adjusted.
  • the size of the molding can be reduced to 0.5mm, so it is possible to smoothly produce soft capsules of a size that can be conveniently taken by children, the elderly and patients with swallowing difficulties. It can be seen that the seamless molding method may be more suitable in terms of producing a small formulation among the objects of the present invention.
  • the capsule surface When using the seamless molding method, one of the important principles is surface tension, and when applying the molding method, a condition arises that the difference in surface tension between the capsule surface and the cooling liquid must be satisfied.
  • the capsule surface In order to achieve smooth disintegration and dissolution of the formulation, the capsule surface must be hydrophilic. Therefore, it is a prerequisite that the capsule surface is composed of a hydrophilic base and the cooling liquid is composed of a hydrophobic base.
  • a general soft capsule consists of a capsule base and an inner liquid, and the capsule base soon constitutes the capsule surface. That is, the capsule base must be a hydrophilic solution to satisfy the prerequisites mentioned above.
  • choline alfoscerate is also a drug that has very high hydrophilicity, when the drug is mixed with water or a hydrophilic solution to form an inner solution and then applied to the seamless molding method, it is mixed with the capsule base solution and cannot form an intact capsule. Occurs.
  • the capsule base solution used in the seamless molding method has a thinner concentration and lower viscosity than the capsule base solution used in the rotary method, so that there is a greater risk of miscibility when the content is hydrophilic.
  • the soft capsule when the soft capsule is molded in this manner, it is necessary to lower the viscosity by administering purified water or the like to the liquid choline alfoscerate raw material having a high viscosity in constituting the content solution. In other words, not only the active ingredients in the content solution but also some moisture are included to make up the total weight. In addition, it may be necessary to add a plasticizer or the like to the capsule base solution for smooth enveloping.
  • the present inventors devised a new method of constructing a soft capsule in order to solve the problem.
  • the contents solution that is, the existing choline alfoscerate soft capsule consisting of two layers, the choline alfoscerate soft capsule in the form of a single layer consisting of a mixture of a gelling agent and the contents solution (English: Chewable capsule, capsule with gummy texture) was molded in a seamless method.
  • FIG. 1 A diagram schematically illustrating the explanation is shown in FIG. 1.
  • the term "single-layer soft capsule" in the present invention means a seamless soft capsule formulation in which a capsule film is not formed.
  • this method When this method is used, improper capsule molding due to mixing described above is solved, and most of the moisture used to form an appropriate viscosity in the drying process after capsule molding can be removed.
  • this method has an effect of significantly suppressing the absorption of water by choline alfoscerate by encapsulating choline alfoscerate in gelatin.
  • due to the physical properties of the liquid choline alfoscerate raw material when the raw material is mixed with the capsule base, it has an effect of improving the plasticity enough to act as a plasticizer, so that additional plasticizers do not need to be added. That is, the hydrophilic choline alfoscerate can be smoothly molded into seamless soft capsules, and the total weight can be effectively reduced.
  • the present invention can solve the problem encountered in storage stability due to the high hydrophilicity and hygroscopicity of the choline alfoscerate raw material generated in the existing formulation. Since the choline alfoscerate active ingredient is uniformly mixed in the capsule, the phenomenon such as crushing due to the migration of the choline alfoscerate active ingredient into the capsule base, which may appear in the existing soft capsules, does not occur. In addition, quality problems such as the content of choline alfoscerate hygroscopicity, which may have appeared in existing tablets, were also solved through the coating process and the use of an additional adsorbent. In particular, by changing the packaging unit into an aluminum foil pouch packaging of one bag, it fundamentally blocks moisture contact and further improves its vulnerability.
  • the gelatinizing agent used in the present invention is gelatin.
  • Gelatin is generally used in the capsule base of soft capsules, and it can be uniformly mixed with choline alfoscerate, which is hydrophilic because it is well soluble in hot water. In addition, it has a property that hardens very quickly at room temperature, so it shows high formability in the seamless molding method. Also, gelatin is economical because its price is low.
  • an active ingredient and a soft capsule component are mixed and prepared.
  • gelatin which is a conventional soft capsule component
  • the flexibility is excessively increased due to the influence of choline alfoscerate, which is an active ingredient, so when the coating process is performed, the shape is easily deformed due to high inadequate hardness. The coating film was damaged and the intended coating effect did not appear.
  • Choline alfoscerate or a salt thereof, which is a pharmacologically active ingredient used in the present invention, is preferably contained in an amount of 40 to 60% by weight of the uncoated tablet. If the weight is less than 40%, the total weight based on 1200mg of the choline alfoscerate active ingredient is about 3000 mg or more, which does not meet the purpose of the present invention to minimize the total weight of the formulation. If the weight exceeds 60%, the choline alfoscerate in the base material The active ingredient ratio is too high, so the soft capsule moldability is poor.
  • the weight of the active ingredient per tablet is preferably about 800 to 1200 mg when taken once a day.
  • the gelling agent used in the present invention absorbs moisture and forms a gel-like semi-solid preparation at a low temperature, and is used to prepare a single-layer soft capsule uncoated tablet.
  • Non-limiting examples of the gelling agent used to prepare the soft capsule uncoated tablet in the present invention may each independently be carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, starch or a mixture thereof, preferably It may be gelatin.
  • the content of the gelling agent may be 50 to 80% by weight based on the total weight of the active ingredient, more specifically 55 to 70% by weight, 65 to 75% by weight may be included, most preferably 60 to 70% by weight Can be included.
  • gelatin If gelatin is used in an excessively low proportion of less than 50% by weight, its moldability is deteriorated, and when gelatin is used in an excessively high proportion of more than 80% by weight, it does not meet the purpose of the present invention to minimize the total weight of the formulation. do.
  • the curing agent used in the present invention refers to a material that helps to harden or thicken other materials, and is used to increase the hardness of a single-layer soft capsule.
  • Non-limiting examples of the curing agent that can be used to prepare the soft capsule uncoated tablet in the present invention may each independently be magnesium aluminate, calcium silicate, microcrystalline cellulose, colloidal silicon dioxide, light anhydrous silicic acid, or a mixture thereof.
  • colloidal silicon dioxide is most preferred.
  • the content of the curing agent may be included in an amount of 10 to 25% by weight based on the total weight of the uncoated soft capsule pharmaceutical composition, and more specifically, 10 to 20% by weight, and 15 to 25% by weight. Most preferably, it may contain 10 to 15% by weight.
  • the content of the curing agent is less than 10% by weight, the hardness improvement through moisture drying may not be appropriate, resulting in poor moldability and stability. If it is more than 25% by weight, the hardness of the formulation is too high and the proportion of the gelling agent decreases during molding. As a result, problems such as not being molded into an appropriate shape may occur.
  • choline alfoscerate single-layer soft capsules using a seamless molding method are uncoated, and the uncoated tablet is first coated with a water-soluble polymer to prepare an immediate-release formulation.
  • a second coating is performed by mixing some of the immediate-release preparations with an insoluble polymer and a water-soluble polymer to provide a sustained-release preparation in which a sustained-release coating layer is formed on the surface of the soft capsule.
  • the water-soluble polymer used in the first coating was hypromellose, and Opadry ® 03K19229 was used as a product.
  • Hypromellose is effective in blocking contact with moisture in the air because hypromellose has low hygroscopicity and its coating film is dense when coated.
  • the water-soluble polymer used in the secondary coating was povidone, and Kollicoat® IR was used as a product.
  • the insoluble polymer used in the secondary coating was polyvinyl acetate, and Kollicoat ® SR was used as the product.
  • the anti-adhesion agent used for coating is talc, an excipient that is generally used as an anti-adherence agent during coating by preventing adhesion between formulations.
  • the present inventors For the purpose of blocking moisture, the present inventors sprayed a primary coating solution containing a moisture barrier agent by different weights, and conducted an experiment to compare the moisture absorption barrier effect according to the spray amount and to select a suitable spray amount. As a result of the implementation, it was confirmed that an appropriate moisture absorption blocking effect appeared when coating at least 3% by weight of the uncoated tablet weight.
  • the sustained-release technology of oral formulations includes a method of controlling release through drug coating and controlling the thickness of the coating layer, a microencapsulation method in which a drug is encapsulated in micro-units of hydrophobic particles, a matrix system method that causes sustained release of a drug through gel formation, and insoluble.
  • a method of releasing drugs in small amounts by osmotic pressure using a polymer a method of forming a complex by combining chemical substances such as drugs and salts so that their dissolution slowly occurs due to poor solubility, and a drug-
  • a drug- There are an ion exchange resin method that forms a resin complex and allows the drug to be released depending on pH or electrolyte concentration, and an Oros method that artificially creates a fine gap in the drug and allows the drug to be slowly released by osmotic pressure.
  • the most suitable sustained-release technology for soft capsules was selected to allow the drug to be released in small amounts by osmotic pressure by coating an insoluble polymer.
  • the technology is characterized by forming a sustained-release coating layer in which an insoluble polymer and a water-soluble polymer are mixed in a specific ratio on the surface of the formulation, so that a small amount of the drug is released by osmotic pressure into the fine pores in which some water-soluble polymers of the membrane are dissolved.
  • the ratio of the insoluble polymer is increased and the ratio of the water-soluble polymer is decreased.
  • the release rate of the drug is controlled according to the pore formation rate according to the ratio of the water-soluble polymer and the weight of the sustained-release coating layer, it is necessary to control the weight of the coating layer and the ratio of the water-soluble polymer so that the release of the drug can be sustained for 24 hours.
  • the present inventors first controlled the drug release rate through the control of the water-soluble polymer ratio, and then secondarily controlled the drug release rate more precisely through the control of the weight of the sustained-release coating layer.
  • the elution pattern was confirmed in a ratio of 1:2 to 1:5, most preferably 1:3 to 1:4.
  • the dissolution of the drug was continued for the most close to 24 hours.
  • the dissolution of the drug continuously appeared for about 24 hours when coating by about 10% of the uncoated tablet weight.
  • talc was used as an anti-adhesive agent because of the characteristics of the sustained-release coating base used, adhesive strength was created during the drying process and the capsules could stick together during coating. The proportion of talc that does not adhere is also an important point to be adjusted.As a result of comparing and spraying coating liquids with different weights of talc added to check for adhesion between soft capsules, talc is at a ratio of 40% by weight or more of the weight of the sustained-release coating layer. When included, it could be confirmed that the coating process proceeded smoothly without adhesion.
  • Non-limiting examples of water-soluble polymers used as part of the first moisture barrier coating and the second sustained release coating layer in the present invention are each independently hydroxypropylethylcellulose, hypromellose, poloxamer, polyvinyl alcohol, polyethylene glycol, propylene It may be glycol, povidone or mixtures thereof.
  • As the water-soluble polymer hypromellose as the first coating and povidone as the second coating are preferable.
  • Non-limiting examples of the insoluble polymer used for the secondary coating may each independently be ethyl cellulose, polyvinyl acetate, methacrylic acid copolymer, or a mixture thereof. Polyvinyl acetate is preferable as the insoluble polymer.
  • Non-limiting examples of the anti-adhesive agent used for coating in the present invention may each independently be talc, microcrystalline cellulose, corn starch, or a mixture thereof, and most preferably talc.
  • a plurality of immediate-release soft capsules and a plurality of sustained-release soft capsules produced through coating using the above-described single-layer soft capsule as an uncoated tablet are mixed in a predetermined ratio as a unit.
  • a dissolution test was carried out by applying 900 mL of water eluate each, and a paddle method of 50 revolutions per minute (10 revisions of the Korean Pharmacopoeia, dissolution test method 2).
  • the dissolution rate of the active ingredient was 25-45% after 1 hour, 45-65% after 8 hours, and 90% or more after 24 hours, which means that a formulation in a form suitable for the purpose was invented.
  • the components were added and heated to 60 °C or higher to uniformly mix, and then the prepared mixture was put on an aluminum disk, solidified into a film, and sufficiently dried using an oven.
  • the ingredients are added according to the ingredients and contents shown in Table 3 below, heated to 60°C or higher, and uniformly mixed, and then prepared. The resulting mixture was molded using a seamless soft capsule molding machine.
  • Classification Ingredient (unit: mg) F1 F2 F3 F4 F5 Remark Active ingredient Choline alfoscerate 1200.0 1200.0 1200.0 1200.0 1200.0 Gelling agent gelatin 200.0 400.0 600.0 800.0 1000.0 Excipient Purified water 4000.0 4000.0 4000.0 4000.0 4000.0 Dried in process Molded or not X X O O O Whether it is hardened through gelation Whether the shape is uniform - - X O ⁇ Whether it is molded into a uniform sized sphere
  • the content of the gelling agent may be 50 to 80% by weight based on the total weight of the active ingredient, and more specifically 55 to 70% by weight, 65 to 75% by weight may be included, but according to the result, 60 to 70% by weight When included, it was found that flexibility and moldability appear most preferably.
  • the sum of the weight of purified water and choline alfoscerate and the ratio of gelatin is about 1 to 6 to 1 to 7, a single-layer seamless soft capsule can be properly molded.
  • the ingredients are added and heated to 60°C or higher to uniformly mix, and then the prepared mixture is put on an aluminum disk to solidify into a film, and then sufficiently dried using an oven. .
  • choline alfoscerate can act as a plasticizer. Since the flexibility of the gelatin and choline alfoscerate mixture decreases significantly when colloidal silicon dioxide is added over a certain ratio, if the flexibility is excessively increased due to choline alfoscerate, excipients with strong adsorption power such as the relevant excipient are used as a curing agent. It can be seen that the problem can be solved by offsetting the flexibility of choline alfoscerate.
  • Preparation Examples 9 to 11 showed that the colloidal silicon dioxide was not folded and the elongation was very low, indicating that the most desirable effect was exhibited in terms of stabilizing the formulation.
  • the curing agent is preferable when it contains 10 to 25% by weight based on the total weight of the active ingredient, and more specifically, 10 to 20% by weight, and 15 to 25% by weight. I can. However, it is most preferable to include 10 to 15% by weight of the curing agent, since it is possible to minimize the size of the formulation and to control the release characteristics when the curing agent is contained in the smallest amount within the range that guarantees formulation moldability and stability. .
  • Preparation Example 8 after uniformly mixing according to the components and contents shown in Table 7 to prepare a coating solution, the prepared coating solution was subjected to a film coating process for a certain period of time using a pan coater.
  • Coating layer Classification Ingredient (unit: g) Manufacturing Example 12 Manufacturing Example 13 Manufacturing Example 14 Manufacturing Example 15 Remark 1st coating 1st coating base Opadry ®03K19229 150.0 150.0 150.0 150.0 2nd coating 2nd coating base Kollicoat ®SR 30D 300.0 300.0 300.0 300.0 300.0 Dry weight (30% by weight of dispersion) 2nd coating base Kollicoat ®IR 60.0 60.0 60.0 60.0 Anti-adhesion agent Talc 150.0 300.0 450.0 600.0 Plasticizer Triethyl citrate 40.0 40.0 40.0 40.0 Total weight of coating layer 700.0 850.0 1000.0 1150.0
  • Preparation Examples 12 to 15 The formulation of Preparation Example 8 coated with the coating solution was used, and the coating process using the coating solution was carried out by pan coating, and Preparation Example 10 was used as the soft capsule to be tested, and the supply air temperature was 50 ⁇ 2°C, It was carried out under the conditions of an exhaust temperature of 35 ⁇ 2° C., a fan speed of 12 rpm, and a pump speed of 2 rpm. Whether or not sticking between soft capsules occurred during coating was determined through the naked eye, and the measurement results are shown in Table 8 below.
  • choline alfoscerate, gelatin, colloidal silicon dioxide, and purified water were heated to 60°C or higher and uniformly mixed.
  • the prepared mixture was molded using a seamless soft capsule molding machine, and the size was adjusted so that the weight after drying was about 37.3 mg. Because colloidal silicon dioxide may be precipitated during molding, the mixture was continuously mixed, and the molded capsules were sufficiently dried so that the loss on drying ratio was 3% or less.
  • Opadry ® 03K19229 as a moisture barrier agent was uniformly mixed with 70% ethanol to prepare a coating solution in a weight ratio of 10%.
  • the prepared coating solution was film-coated in a conventional manner using a pan coater to prepare a choline alfoscerate immediate-release single-layer soft capsule.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Remark Active ingredient Choline alfoscerate 20.00 20.00 20.00 20.00 20.00 Gelling agent gelatin 13.33 13.33 13.33 13.33 13.33 Hardener Colloidal silicon dioxide 4.00 4.00 4.00 4.00 4.00 Aeroperl ®300
  • Excipient Purified water 66.67 66.67 66.67 66.67 66.67 Dried in process Moisture barrier Opadry ®03K19229 - 1.33 2.00 2.67 3.33 10% solution
  • Example 1 to 5 For the immediate-release single-layer soft capsules prepared in Examples 1 to 5, an accelerated test was performed to confirm the moisture absorption blocking effect and property change according to the coating weight of the moisture barrier agent.
  • control drug 1 Chong Kun Dang glatirin soft capsule, Chong Kun Dang
  • control drug 2 Gria tablet, Korea Prime Pharmaceutical
  • the range of moisture content change was suitable for a timely stability. That is, the moisture barrier agent must be coated with at least 3% by weight or more relative to the total weight of the pharmaceutical composition including the active ingredient, the gelling agent, and the curing agent to exhibit an appropriate moisture absorption blocking effect, and the coating and moisture absorption blocking effect up to 10% by weight can be smoothly achieved. It can be seen that it is done. Therefore, the content of the moisture barrier agent may be 3 to 10% by weight based on the total weight of the pharmaceutical composition, more specifically 4 to 7% by weight, 6 to 9% by weight, most preferably Examples 3 and 4 It may be 5 to 8% by weight based on.
  • the stability of the soft capsules produced in the present invention is compared to the existing formulations, as problems such as changes in properties such as capsule crushing in reference drug 1 and strong hygroscopicity under accelerated conditions appearing in reference drug 2 do not appear in the examples. You can see that it is more excellent.
  • sustained-release coating was performed as a second coating process.
  • Kollicoat® SR water-insoluble polymer
  • Kollicoat® IR water-soluble polymer
  • talc talc
  • triethyl citrate were uniformly mixed according to the content to prepare a coating solution.
  • the prepared coating solution was film-coated on the soft capsules of Example 4 in a conventional manner using a pan coater to form a sustained-release coating layer, thereby preparing a choline alfoscerate sustained-release single-layer soft capsule.
  • Example 4 Remark Immediate control agent Immediate-release capsule Formulation of Example 4 40.00 40.00 40.00 40.00 40.00 Slow-release coating layer Water insoluble polymer Kollicoat ®SR 0.81 1.63 2.44 3.25 4.06 Dry weight (30% by weight of dispersion) Water soluble polymer Kollicoat ®IR 0.22 0.43 0.65 0.87 1.08 Anti-sticking agent Talc 1.20 2.40 3.60 4.80 6.00 Plasticizer Triethyl citrate 0.22 0.43 0.65 0.87 1.08
  • a plurality of sustained-release single-layer soft capsules (20 mg as choline alfoscerate) prepared in Examples 6 to 10 were prepared, and the elution pattern according to the weight of the sustained-release coating layer was obtained for 40 capsules (total 800 mg as choline alfoscerate).
  • a comparative dissolution test was conducted to confirm. As test conditions, a dissolution test was performed by applying a paddle method of 900 mL of water eluate and 50 rotations per minute (Korean Pharmacopoeia 10 revision, dissolution test method 2), and the results are shown in FIG. 4.
  • the sustained-release coating layer may be 5 to 40% by weight based on the total weight of the pharmaceutical composition excluding the sustained-release coating layer, more specifically 10 to 25% by weight or 20 to 35% by weight, most preferably 15 It can be seen that excellent effects appear when included in to 30% by weight.
  • Example 4 20 capsules of the immediate-release single-layer soft capsule prepared in Example 4 (400 mg as choline alfoscerate) and 40 capsules of the sustained-release single-layer soft capsule prepared in Example 9 (800 mg as choline alfoscerate) as a unit .
  • a comparative dissolution test was conducted to confirm the dissolution pattern under various pH conditions.
  • the eluate conditions were water, pH 1.2, pH 4.0, and pH 6.8, respectively, and the paddle method of 50 revolutions per minute (10 revisions of the Korean Pharmacopoeia, dissolution test method 2) was applied to conduct a dissolution test, and the results are shown in Figs. Shown in.
  • Example 4 Based on the formulation of Example 4 showing the best effect among the immediate-release single-layer soft capsules containing choline alfoscerate, an immediate-release single-layer soft capsule additionally containing donepezil hydrochloride was prepared. Donepezil hydrochloride is more preferably included in an immediate-release preparation than in a sustained-release preparation for rapid pharmacological effect.
  • Donepezil hydrochloride and the remaining components were additionally added according to the compositions of Examples 11 to 15 in Table 12 below. It was prepared in the same manner as in Examples 1 to 5, except that donepezil hydrochloride was additionally included.
  • donepezil hydrochloride is a drug that requires rapid drug release and is preferably included in all of the immediate-release preparations, so the immediate-release preparations and sustained-release preparations corresponding to the test group of Test Example 7
  • 20 capsules of fast-release single-layer soft capsules equivalent to 400 mg as choline alfoscerate were used as 1 unit, and the content of donepezil hydrochloride was adjusted according to the composition.
  • the content of donepezil hydrochloride per capsule of the immediate release agent is specifically preferably 1 to 7% by weight based on the total weight of choline alfoscerate.

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Abstract

La présente invention concerne une nouvelle forme galénique d'une composition pharmaceutique contenant de l'alfoscérate de choline. En outre, la présente invention concerne des compositions pharmaceutiques contenant de l'alfoscérate de choline permettant à la fois une libération rapide et une libération prolongée, et l'administration par voie orale de telles compositions pharmaceutiques à la fois à libération rapide et à libération prolongée permet d'obtenir une efficacité pharmaceutique suffisante par une seule dose quotidienne.
PCT/KR2020/012472 2019-10-22 2020-09-16 Préparation de petite taille à libération prolongée destinée à être administrée par voie orale contenant de l'alfoscérate de choline WO2021080185A1 (fr)

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KR101533286B1 (ko) 2013-12-09 2015-07-03 주식회사한국파마 콜린알포세레이트를 함유하는 경구용 약학 조성물 및 이의 제조 방법
KR101796628B1 (ko) 2016-05-25 2017-11-10 한국프라임제약주식회사 콜린알포세레이트를 함유하는 방습성 정제, 및 이의 제조방법

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KR20140094679A (ko) * 2013-01-14 2014-07-31 주식회사 바이오파마티스 콜린 알포세레이트 또는 이의 약학적으로 허용되는 염을 포함하는 방출 조절형 약학 조성물 및 이의 제조방법
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