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WO2021080184A1 - Composition pharmaceutique de petite taille et à libération prolongée comprenant de l'alfoscérate de choline - Google Patents

Composition pharmaceutique de petite taille et à libération prolongée comprenant de l'alfoscérate de choline Download PDF

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Publication number
WO2021080184A1
WO2021080184A1 PCT/KR2020/012471 KR2020012471W WO2021080184A1 WO 2021080184 A1 WO2021080184 A1 WO 2021080184A1 KR 2020012471 W KR2020012471 W KR 2020012471W WO 2021080184 A1 WO2021080184 A1 WO 2021080184A1
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Prior art keywords
pharmaceutical composition
sustained
release
weight
agent
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English (en)
Korean (ko)
Inventor
김성엽
송희용
김병진
최연웅
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Korea United Pharm Inc
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Korea United Pharm Inc
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • 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
    • A61K9/485—Inorganic 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 sustained-release pharmaceutical composition containing choline alfoscerate as an active ingredient, and to a pharmaceutical composition prepared in a small dosage form while having sustained-release properties.
  • 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.
  • Choline alfoscerate an active ingredient in the present invention, is a compound also called L- ⁇ -glyceryl phosphoryl choline (L-GPC), and has the following chemical structure.
  • L-GPC L- ⁇ -glyceryl phosphoryl choline
  • choline alfoscerate formulations are commercially available in soft capsules and tablets with a dose of 3 times a day, but the amount of active ingredient administered is choline alfoscerate once, which is 400 mg, which is a large size (large Treaty standard long axis: 16.1mm, short axis: 8.5mm, thickness: 8.5mm, reference drug: Chong Kun Dang gliatyrin soft capsule)
  • the number of doses is often 3 times, so there is insufficient part to satisfy patients' adherence.
  • Prior Art Document 1 Korean Patent Laid-Open Patent No. 10-2013-0010044
  • a sustained-release tablet was developed in a form in which particles coated with a sustained-release coating were prepared by spraying with and then the particles were tableted together with an additional excipient.
  • the tablet size is too large, it is very weak in dosage convenience, and the production yield is low because the productivity problem that occurs in the sustained-release coating process cannot be solved. Therefore, there are still problems in terms of economy and convenience in taking patients.
  • Prior Art Document 2 Korean Patent Laid-Open Patent No. 10-2015-0066937
  • the weight of the formulation is reduced, the difficulty of the manufacturing process is lowered, and the process steps can also be simplified.
  • the total weight of the tablet is lowered, the size of the formulation is reduced, so that the convenience of taking medicine can be increased.
  • triple coating is performed as a method to block the inflow of moisture in the air after uncoated production.
  • the difficulty of the process is very high to maintain the stability of each layer while coating the uncoated tablet three times, and the calcium silicate used as an adsorbent is also an excipient that often causes tableting disorders due to its very low tabletting properties, so this is also an efficient method for mass production. I can't.
  • Prior Art Document 3 is a film-coated tablet coated with hydroxypropylmethylcellulose and polyvinyl alcohol by adsorbing choline alfoscerate on magnesium metasilicate and tableting uncoated tablets.
  • magnesium metasilicate aluminate used is 62.5% compared to the active ingredient, the total weight is large, and the size of the tablet increases, so there is still a weak side in terms of ease of administration.
  • One formulation of the pharmaceutical composition according to the present invention is a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising a sustained-release agent and an adsorbent, based on the total weight of the pharmaceutical composition.
  • the active ingredient is characterized in that it comprises 30 to 40% by weight, the sustained-release base agent is 30 to 50% by weight, and the adsorbent comprises 2 to 4% by weight.
  • the sustained-release agent is intended to exhibit a sustained-release effect for a long time and serves to maintain a constant dissolution rate, and if it is out of the above range, it may dissolve too quickly and the lasting effect may be short, or sufficient dissolution may not occur while remaining in the body. .
  • the adsorbent is intended to reduce tabletting disorders during tablet manufacturing, and if it is included in less than 2% by weight, obstacles may frequently appear during the tableting process such as low flowability and sticking during tableting, and when included in excess of 4% by weight, capping, It is not preferable because it may cause obstacles in the tableting process of uncoated tablets such as laminating.
  • the sustained-release base is one or two selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, and hydroxypropylcellulose A mixture of the above can be used, and the most desirable effect is obtained when using polyethylene oxide.
  • the adsorbent may be one or a mixture of two or more selected from the group consisting of calcium silicate, meglumine, and colloidal silicon dioxide.
  • the pharmaceutical composition is a tablet having a total weight of 30 to 40 mg, has excellent stability, and has a very small tablet size, so even if a plurality of unit formulations are included in one package per oral dosage unit, the medication convenience is excellent.
  • a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient a tablet layer comprising an active ingredient, an excipient, an adsorbent, and a sustained-release base agent And it may be to include a sustained-release coating layer containing a sustained-release base.
  • the content of the sustained-release agent in the tablet layer is preferably 10 to 20% by weight based on the total weight of the pharmaceutical composition, and more preferably 13 to 17% by weight.
  • the formulation further includes a sustained-release base agent in the sustained-release coating layer, a more excellent sustained-release effect may be exhibited even in a small size.
  • the content of the sustained-release agent in the sustained-release coating layer may be 5 to 15% by weight, more preferably 7 to 10% by weight, based on the total weight of the pharmaceutical composition.
  • the sustained-release base of the tablet layer may be a generally used sustained-release base, but in the present invention, hydroxypropylmethylcellulose was used.
  • the sustained-release bases that may be included in the sustained-release coating layer, excellent effects are exhibited in combination with the sustained-release bases included in the purification layer: ethyl methacrylate/ethacrylic acid chlorotrimethylammonium ethyl copolymer, ethyl cellulose, and polyvinyl acetic acid. It may be one or a mixture of two or more selected from the group consisting of.
  • the active ingredient is characterized in that it contains 35 to 45% by weight based on the total weight of the pharmaceutical composition, and the total weight is 55 to 65mg, and exhibits excellent sustained-release effect even though it is prepared as a very small sized tablet.
  • the present invention is a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, the active ingredient is filled inside the soft capsule film, and the soft capsule includes a capsule base, a plasticizer, and a sustained-release base. Another type of pharmaceutical composition is provided.
  • the sustained-release base agent may preferably be included in 10 to 30% by weight, more preferably 15 to 25% by weight based on the total weight of the pharmaceutical composition.
  • the sustained-release base is one or two selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, and hydroxypropylcellulose. The above mixture can be used.
  • the plasticizer may be included in 7 to 20% by weight based on the total weight of the capsule base, more preferably 8 to 15% by weight.
  • the plasticizer is characterized in that it is one or a mixture of two or more selected from the group consisting of concentrated glycerin, propylene glycol, sorbitol, and polyethylene glycol.
  • the present invention provides a pharmaceutical composition in a single-layer dosage form prepared in a seamless form as another pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition may further include a gelling agent, a curing agent, and a sustained-release agent in addition to the active ingredient as needed, and as a seamless formulation, it is characterized in that it is formed in a single layer while having characteristics similar to that of a soft capsule, so that it is simple to manufacture and has excellent stability. It is done.
  • the gelling agent may be used by mixing one or two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch.
  • the curing agent may use one or two or more silicon-based compounds or cellulose derivatives containing silicon having excellent physical properties in terms of adsorption properties.
  • magnesium aluminate As non-limiting examples of the silicon-based compound or cellulose derivative of the curing agent, magnesium aluminate, calcium silicate, microcrystalline cellulose, colloidal silicon dioxide, and light anhydrous silicic acid may be used.
  • the sustained-release base is one or two selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, and hydroxypropylcellulose The above can be mixed and used.
  • the curing agent is preferably contained in an amount of 30 to 80% by weight, more specifically 40 to 60% by weight, 50 to 70% by weight may be included, and most preferably 50 to 60% by weight Can be included.
  • the curing agent is necessary to maintain the moldability and stability of a seamless single-layer soft capsule formulation formed by mixing choline alfoscerate and a gelling agent. If the content is too low compared to the gelling agent, the capsule is not sufficiently cured to maintain its shape. It becomes difficult, and if it is too high, the capsule may not be smoothly molded in the manufacturing process.
  • sustained-release base agent may preferably be included in 30 to 60% by weight based on the total weight of the pharmaceutical composition, more specifically, 30 to 50% by weight, may be included in 40 to 60% by weight, most preferably 40 To 45% by weight may be included.
  • the present invention is a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, the active ingredient is filled inside the soft capsule film, and the sustained release including a sustained-release base on the surface of the soft capsule film It provides a pharmaceutical composition, characterized in that the chemical coating layer is formed.
  • This formulation is a sustained-release coating layer formed with a coating solution containing a sustained-release agent on the surface of a conventional soft capsule film, and is a sustained-release pharmaceutical composition with low adhesion, and exhibits excellent stability that does not cause denaturation even during long-term storage.
  • the soft capsule may be used by selecting one or two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch.
  • the sustained-release base may be used by selecting one or two or more selected from the group consisting of ethyl methacrylate ⁇ chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid.
  • a separation coating layer including a separator obtained by mixing one or two or more selected from the group consisting of hydroxypropylmethylcellulose, povidone, and polyvinyl alcohol is formed.
  • the weight ratio of the separator and the sustained-release agent may be preferably 1:5 to 1:10, more preferably 1:6 to 1:8.
  • the separation coating layer serves to protect the soft capsules vulnerable to moisture from being dissolved in the solvent of the sustained-release agent to prevent adhesion, and the separation agent and the sustained-release agent preferably maintain the weight ratio. If the separator is too small, the capsule film may melt and stick, and if it is too high, the uniformity of the sustained-release coating may decrease.
  • sustained-release base may be included in 10 to 30% by weight, more preferably 15 to 25% by weight, based on the total weight of the pharmaceutical composition in order to exhibit a desirable sustained-release effect.
  • the choline alfoscerate sustained-release small formulation for oral administration prepared according to the present invention is to simultaneously orally administer a plurality of formulations in a single dosage unit, and the conventional oral administration formulation is taken once a day. It is characterized by being able to achieve a sufficient effect just by itself. The size of individual formulations has been minimized so that dozens of formulations are administered at the same time, so that discomfort is not felt. It is possible to contain all of the formulations. In addition, each formulation is designed to maintain a certain dissolution pattern despite its very small size, so it is possible to achieve a quick pharmacological effect even with fewer side effects. You can expect improvement.
  • FIG. 1 shows the results of a dissolution test in water performed with 100 tablets (1200 mg as choline alfoscerate) as one unit for the small tablets prepared in Examples 1 to 6 and Comparative Example 1.
  • FIG. 1 shows the results of a dissolution test in water performed with 100 tablets (1200 mg as choline alfoscerate) as one unit for the small tablets prepared in Examples 1 to 6 and Comparative Example 1.
  • FIG. 2 shows the results of a dissolution test in water performed with 50 tablets (1200 mg as choline alfoscerate) as one unit for the small tablets prepared in Examples 7 to 9 and Comparative Example 2.
  • FIG. 2 shows the results of a dissolution test in water performed with 50 tablets (1200 mg as choline alfoscerate) as one unit for the small tablets prepared in Examples 7 to 9 and Comparative Example 2.
  • FIG. 3 shows the results of a dissolution test in water performed with each 40 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 10 to 15 and Comparative Example 3.
  • FIG. 4 shows the results of a dissolution test in water performed with each 100 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 16 to 21 and Comparative Example 4.
  • FIG. 4 shows the results of a dissolution test in water performed with each 100 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 16 to 21 and Comparative Example 4.
  • FIG. 5 shows the results of a dissolution test in water performed with each 50 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 22 to 24 and Comparative Example 5.
  • FIG. 5 shows the results of a dissolution test in water performed with each 50 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 22 to 24 and Comparative Example 5.
  • choline alfoscerate sustained-release small tablets according to Examples 1 to 6 and Comparative Example 1 were prepared through tableting.
  • the preparations prepared for each group may contain 1200 mg of choline alfoscerate per unit (100 tablets).
  • a comparative dissolution test was conducted to confirm the effect of sustained-release drugs according to the type of sustained-release agent added in the tablet.
  • the dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did.
  • the test results are shown in FIG. 1.
  • the formulations of Examples 1 to 6 are tablet formulations, and in order to solve the problem of tableting disorders due to the hygroscopicity of choline alfoscerate, 2 to 4% by weight of an adsorbent is used based on the total weight of the tablet.
  • an adsorbent calcium silicate or a material having similar physical properties, for example, meglumine, colloidal silicon dioxide, etc. may be used, but the present invention is not limited thereto.
  • the adsorbent is to reduce tableting difficulties and stability problems of tablets that may occur due to the strong hygroscopicity of the main component during tableting. If the adsorbent is contained in less than 2% by weight, tableting problems such as sticking during the manufacture of uncoated tablets, tableting It is not suitable because quality problems including properties due to the absorption of moisture in the air of the post tablet may frequently occur. On the other hand, if the adsorbent exceeds 4% by weight and contains too much, obstacles may occur during the process of processing uncoated tablets such as capping and laminating, and since the total dosage of the pharmaceutical composition per oral dosage unit increases, it is inconvenient to pass the neck. And the administration time is prolonged, so the patient's convenience in medication may be degraded.
  • Examples 1 to 3 exhibited a sustained-release effect for a long time and the dissolution rate was constantly increased, resulting in the most desirable results. Accordingly, when the total weight of the tablet contains 30 to 40% by weight of the active ingredient choline alfoscerate, and 30 to 50% by weight of the sustained-release base agent, based on the total weight of the pharmaceutical composition, the sustained-release effect is I could see that it appeared. At this time, when using hydroxypropylmethylcellulose (hypromellose 2208) or polyethylene oxide as a sustained-release base, the most desirable effect was exhibited. It was confirmed that most of the formulations prepared in Examples 1 to 6 were eluted after a maximum of about 6 hours.
  • the main component, adsorbent, excipient, sustained-release agent, and lubricant were mixed and tableted, and then the coating base was mixed with water to prepare a coating solution having a concentration of 10%. Thereafter, the coating solution was sprayed onto tablets tableted in a conventional manner using a pan coater to prepare choline alfoscerate sustained-release small film-coated tablets according to Examples 7 to 9 and Comparative Example 2.
  • the preparations prepared for each group were made to contain 1200 mg of choline alfoscerate per unit (50 tablets).
  • a comparative dissolution test was conducted to confirm the drug sustained-release effect according to the type of sustained-release coating base coated on the tablet surface.
  • the dissolution test was conducted on 50 tablets (1200 mg as choline alfoscerate) for 1 unit of preparation prepared by group, and as test conditions, 900 mL of water eluate, paddle method with 50 rotations per minute (Revised Korean Pharmacopoeia 11, method 2 ) Was applied. The test results are shown in FIG. 2.
  • the formulations of Examples 7 to 9 are coated tablet formulations coated with a sustained-release base agent on the surface of a tablet containing choline alfoscerate as an active ingredient, and the total weight is 55 to 65 mg, based on the total weight of the pharmaceutical composition including the coating layer, It contains 35 to 45% by weight of an active ingredient.
  • the sustained-release agent may be included in both the tablet and the coating layer. It is preferable to use hydroxypropylmethylcellulose or polyethylene oxide as the sustained-release agent included in the tablet, but when the sustained-release agent in the tablet is used alone, the sustained-release effect was found to be insufficient to sustain the drug release time for a long time. . It is believed that because of the strong hydrophilicity of choline alfoscerate, even if a sustained-release agent is included, the drug is rapidly released into the eluate due to strong affinity with water. As the content of the active ingredient is contained twice as compared to Examples 1 to 6, the reason is that sufficient dissolution control is not performed for the entire amount of the increased active ingredient just by including a sustained-release agent in the tablet. Is judged.
  • a formulation form was devised that additionally includes a sustained-release agent in the coating layer outside the tablet surrounding the tablet.
  • the coating layer including the sustained-release agent is included in the second coating layer after first sub-coating the uncoated tablet so that the sustained-release agent does not interact with the active ingredient in the tablet.
  • the sustained-release base included in the secondary coating layer may be selected from the group consisting of ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid, and such a sustained-release coating base may be additionally used.
  • the sustained-release base included in the tablet is preferably included in 10 to 20% by weight based on the total weight of the pharmaceutical composition including the coating layer, and the sustained-release base included in the coating layer is preferably included in 5 to 15% by weight.
  • the sustained-release characteristics of the pharmaceutical composition may be deteriorated or excessive.
  • Choline alfoscerate sustained-release according to Examples 10 to 15 and Comparative Example 3 including a capsule base, a plasticizer, and a sustained-release agent as a soft capsule film, including the main component and excipient in the content solution according to the ingredients and contents shown in Table 3 below.
  • Castle small soft capsules were prepared.
  • the soft capsule formulation according to the present embodiment is characterized in that the tablet size is minimized, unlike the conventional soft capsule, so that it has excellent medication convenience and high moisture stability.
  • the preparations prepared for each group were made to contain 1200 mg of choline alfoscerate per unit (40 capsules).
  • a comparative dissolution test was conducted to confirm the effect of sustained-release drugs according to the type of sustained-release agent added in the soft capsule film.
  • the dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did.
  • the test results are shown in FIG. 3.
  • Examples 10 to 15 are characterized in that the choline alfoscerate formulation is filled inside the soft capsule film, and the soft capsule includes a plasticizer and a sustained-release base in addition to the capsule base.
  • the capsule base 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. Gelatin was used.
  • the sustained-release base included in the soft capsule is 1 selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate/ethacrylic acid chlorotrimethylammonium ethyl copolymer, and hydroxypropylcellulose. It may be a species or a mixture of two or more.
  • the content of the sustained-release agent is preferably 10 to 30% by weight based on the total weight of the pharmaceutical composition including the soft capsule film.
  • the sustained-release effect cannot be achieved, and when it exceeds 30% by weight, the viscosity of the capsule base solution becomes too high. It can cause disturbances during the molding process.
  • the plasticizer may be one or a mixture of two or more selected from the group consisting of concentrated glycerin, propylene glycol, sorbitol, and polyethylene glycol, and is preferably contained in 7 to 20% by weight of the total weight of the capsule base. If the plasticizer is less than the above range, the capsule is liable to break due to insufficient flexibility, and if the plasticizer exceeds the above range, the size increases as the weight of the formulation increases, which is not preferable in terms of ease of medication.
  • Examples 10 to 15 are formulations containing an active ingredient in a film made of a capsule base and a sustained-release base.
  • the soft capsule formulation containing a film like the corresponding formulation, must have a hydrophilic property on the surface of the film in order to smoothly disintegrate in the body to achieve dissolution of the contents.
  • choline alfoscerate contained in the film as an inner solution is also a drug having high hydrophilicity, in the case of a general soft capsule form as in Examples 10 to 15, the solution may affect the stability of the film during long-term storage. . In order to prevent this problem, not only the type and content of the film, but also the composition of the content solution is limited.
  • the applicant of the present invention has studied the choline alfoscerate soft capsule formulation in more depth, and unlike the conventional soft capsule consisting of an inner liquid and a film, there is no distinction between layers and does not contain liquid. It has developed a seamless soft capsule consisting of a single layer that does not change its properties.
  • the seamless type of soft capsule molding showed more excellent production stability and productivity than the generally used rotary type soft capsule molding, so the corresponding molding method was adopted.
  • the choline alfoscerate soft capsule formulation molded in a seamless manner, a new problem that did not occur in the existing soft capsule formulation was discovered.
  • a semi-solid film base made of a low moisture content is used in the process of filling the contents with a film made of a capsule base such as gelatin, so even if the contents have strong hydrophilicity, the manufacturing process There was no problem of disintegration of the formulation due to the mixing of the film base and the inner solution.
  • both the content liquid and the film base must have low viscosity due to the nature of the process so that the molding can occur smoothly. Due to the restrictions as described above, in the case of molding seamless soft capsules, the moisture content in the film base must be increased. However, when the solution of choline alfoscerate, which has strong hydrophilicity, comes into contact with the coating base, the coating is completely miscible with the solution due to the increased moisture content in the coating base, that is, it is not possible to form an appropriate form in which the solution and the coating are separated. I didn't.
  • the applicant of the present invention has repeatedly studied, screened the gelling agent and the curing agent, and combined them in a specific ratio to complete a sustained-release single-layer soft capsule capable of controlling the dissolution of active ingredients while having excellent moldability even when manufactured in a seamless method. Became.
  • the single-layer soft capsule of the present invention has superior long-term storage compared to the conventional soft capsule, which is vulnerable to moisture, and has a smaller size compared to the conventional sustained-release tablet formulation, so that it has excellent medication convenience and a high manufacturing yield.
  • the single-layer soft capsule of the present invention which is prepared in a single layer by mixing all of choline alfoscerate, a gelling agent, a hardening agent, and a sustained-release agent, uses a gelling agent to prepare a capsule film and contains an active ingredient therein.
  • Choline alfoscerate a hydrophilic active ingredient that is difficult to manufacture in a conventional seamless method, differs from the conventional soft capsule formulation and is named as chewable formulation and gummy formulation. It is a novel single-layer soft capsule formulation of a seamless method that contains as an active ingredient and has excellent moldability and stability.
  • the gelling agent one or a mixture of two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch may be used.
  • One or a mixture of two or more selected from the group consisting of calcium silicate, microcrystalline cellulose, colloidal silicon dioxide, and light anhydrous silicic acid may be used.
  • a suitable gelling agent and a curing agent were screened, and in order to find an optimal combination, the content of the curing agent was varied according to the content of the main component and gelatin, and it was confirmed whether or not the flexibility was reduced according to the content of the curing agent in order to form a seamless formulation.
  • gelatin was used as a gelling agent
  • colloidal silicon dioxide was used as a curing agent.
  • the specific combination ratio of the composition used in the test is shown in Table 4 below.
  • Classification Ingredient (unit: mg) F1 F2 F3 F4 F5 F6 Remark Active ingredient Choline alfoscerate 1200.0 1200.0 1200.0 1200.0 1200.0 1200.0 Gelling agent gelatin 800.0 800.0 800.0 800.0 800.0 Hardener Colloidal silicon dioxide 100.0 200.0 300.0 400.0 500.0 600.0 Aeroperl ®300 Excipient Purified water 2000.0 2000.0 2000.0 2000.0 2000.0 2000.0 Dried in process
  • the F4 to F6 is expected to have excellent molding stability since no folding phenomenon occurs.
  • Choline alfoscerate has properties similar to plasticizers that improve flexibility in terms of its physicochemical properties, so when mixed with gelatin and other gelatinizing agents and dried, it has the property of greatly increasing the flexibility of the dried product.
  • the component has high moisture affinity, so even if it is mixed with a gelatinous agent such as gelatin and dried, it strongly absorbs moisture in the air, and the surface of the dried product has a viscous consistency. That is, when manufacturing a seamless single-layer soft capsule, a curing agent that reduces flexibility may be included in order to increase the quality stability of the prepared formulation.
  • most of the hardeners have moisture-proof properties, and thus have the effect of blocking the moisture absorption of choline alfoscerate.
  • the curing agent is preferably 30 to 80% by weight based on the total weight of the gelling agent, more specifically 40 to 60% by weight, 50 to 70% by weight may be included, most preferably 50 It may contain to 60% by weight.
  • the curing agent is included in an amount of less than 30% by weight with respect to the total weight of the gelling agent, as shown in Table 5 above, the flexibility is too high and the elongation rate is high, so that even when dried, the curing is not sufficiently cured, and the soft capsules adhere to each other. May appear.
  • the ratio of the curing agent is low, viscosity and flexibility due to the main component and the gelling agent remain, so that the capsules are not stable in quality, such as being attached to each other or deforming in shape.
  • the hardness of the soft capsules becomes too high, and the proportion of the gelling agent is relatively low, so the process in which the soft capsules must be rapidly hardened by the gelling agent in the molding machine is not smoothly performed, resulting in a spherical shape. It cannot be maintained, and the viscosity of the solution itself to be molded is also strong, and the capsule is molded in a non-uniform size.
  • composition of the sustained-release single-layer soft capsule of the seamless method according to the present invention was derived, and specifically shown in Table 6 below.
  • a choline alfoscerate sustained-release small soft capsule composed of a single layer according to Examples 16 to 21 and Comparative Example 4 containing a main component, a gelling agent, a hardening agent, and a sustained-release agent in the contents according to the ingredients and contents shown in Table 6 below. I did. The preparations prepared for each group were made to contain 1200 mg of choline alfoscerate per unit (100 capsules).
  • a comparative dissolution test was conducted to confirm the effect of sustained-release drugs according to the type of sustained-release agent added in the single-layer soft capsule.
  • the dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did.
  • the test results are shown in FIG. 4.
  • sustained-release base one or two or more types selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethacrylate copolymer, and hydroxypropylcellulose Mixtures can be used.
  • the sustained-release base agent may be included in 30 to 60% by weight based on the total weight of the pharmaceutical composition, and more specifically, 30 to 50% by weight, 40 to 60% by weight may be included, most preferably 40 to 45% by weight Can be included. If the sustained-release agent is out of the above range, the sustained-release effect or pharmacological effect may be reduced.
  • a sustained-release coating layer including a sustained-release agent may be added to the surface of the pharmaceutical composition prepared seamlessly.
  • the seamless formulation is a formulation in which gelatin and an active ingredient are mixed and is vulnerable to moisture, when a coating layer is formed by using an insoluble substance as a sustained-release base, an additional effect of further excellent formulation stability can be obtained in addition to the sustained-release effect.
  • sustained-release base agent water-insoluble cellulose and derivatives thereof may be selectively used.
  • Ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylene methyl cellulose phthalate, etc. can be selectively used by mixing one or two or more.
  • a soft capsule composed of a main component and an excipient as an inner solution, a capsule base and a plasticizer as a soft capsule film was prepared. Thereafter, the coating base was mixed with water to prepare a coating solution of 10% concentration, and the choline alfoscerate sustained-release soft capsule according to Examples 22 to 24 and Comparative Example 5 was sprayed onto the soft capsule in a conventional manner using a pan coater.
  • the preparations prepared for each group are capable of containing 1200 mg of choline alfoscerate per unit (50 capsules).
  • a comparative dissolution test was conducted to confirm the drug sustained-release effect according to the type of sustained-release coating base coated on the surface of the soft capsule.
  • the dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did.
  • the test results are shown in FIG. 5.
  • Examples 22 to 24 are pharmaceutical compositions in which an active ingredient, choline alfoscerate, is filled into a soft capsule film, and a coating liquid containing a sustained-release agent is coated on the surface of the soft capsule film.
  • the pharmaceutical composition is prepared by preparing a capsule film using a capsule base and a plasticizer, filling the inner liquid with an active ingredient and an excipient, and then coating the capsule film with a coating solution containing a sustained-release base.
  • capsule coating one or a mixture of two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch may be used.
  • sustained-release base one selected from the group consisting of ethyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid may be used.
  • the sustained-release base may contain 5 to 15% by weight based on the total weight of the pharmaceutical composition, and if it is out of the above range, the sustained-release may be lowered or the pharmacological effect may not be sufficiently exhibited.
  • the active ingredient and the sustained-release agent are physically contacted to prevent deterioration by interaction, and to prevent adhesion by dissolving in the moisture of gelatin.
  • a coating layer may be further formed.
  • the separation coating layer may include a separator that is one or a mixture of two or more selected from the group consisting of hyproxypropylmethylcellulose, povidone, and polyvinyl alcohol.
  • the separation coating layer made of the separator serves to uniformly form the coating layer during the sustained-release base coating process.
  • the sustained-release bases included in the sustained-release coating layer mainly use a water-soluble solvent when preparing the coating solution. Therefore, as a component included in the separation coating layer, the above separation bases having low reactivity to both the sustained-release base and the active ingredient and excellent in water barrier properties may be selectively used.
  • hydroxypropylmethylcellulose may be most preferably used, and the weight ratio of the separator included in the separation coating layer and the sustained-release agent in the sustained-release coating layer is preferably 1:5 to 1:10. If the content of the separation coating layer is too low, the stability of the formulation may be reduced due to the interaction of the soft capsule film and the sustained-release base, and if it is too high, the tablet formulation becomes large, which may negatively affect the ease of use and inferior economy.

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Abstract

La présente invention concerne une composition pharmaceutique de petite taille et à libération prolongée comprenant de l'alfoscérate de choline utilisé comme constituant efficace et des préparations de diverses formes galéniques utilisant celle-ci. Une préparation d'alfoscérate de choline de petite taille et à libération prolongée, destinée à être administrée par voie orale, préparée selon la présente invention, utilise un substrat à libération prolongée pharmaceutiquement acceptable, et ainsi l'élution d'un médicament est maintenue en continu pendant une longue période, réduisant le nombre de fois où le médicament est administré par jour. L'invention concerne également, en plus de réduire le nombre de fois où un médicament est administré par comparaison avec des préparations classiques, la commodité d'administration qui est améliorée par réduction de la taille des préparations individuelles et une amélioration de l'effet de traitement peut être attendue pour des patients prenant un médicament sur une longue période, par comparaison avec des préparations classiques.
PCT/KR2020/012471 2019-10-22 2020-09-16 Composition pharmaceutique de petite taille et à libération prolongée comprenant de l'alfoscérate de choline Ceased WO2021080184A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
KR20150066937A (ko) * 2013-12-09 2015-06-17 주식회사한국파마 콜린알포세레이트를 함유하는 경구용 약학 조성물 및 이의 제조 방법
KR20160054216A (ko) * 2014-11-06 2016-05-16 환인제약 주식회사 콜린알포세레이트를 함유하는 정제 및 그 제조방법
KR101794573B1 (ko) * 2016-11-22 2017-11-07 이니스트바이오제약(주) 콜린알포세레이트를 포함하는 속방출형 고형제제 및 이의 제조방법
EP3513782A1 (fr) * 2018-01-18 2019-07-24 Universita' Degli Studi Di Camerino Formulations de gel pour l'administration orale des medicaments, notamment à des patients souffrant de dysphagie

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101257918B1 (ko) 2011-07-14 2013-04-30 주식회사 바이오파마티스 콜린 알포세레이트 또는 이의 약학적으로 허용되는 염을 포함하는 서방형 약학 조성물 및 이의 제조방법
KR101796628B1 (ko) 2016-05-25 2017-11-10 한국프라임제약주식회사 콜린알포세레이트를 함유하는 방습성 정제, 및 이의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
KR20150066937A (ko) * 2013-12-09 2015-06-17 주식회사한국파마 콜린알포세레이트를 함유하는 경구용 약학 조성물 및 이의 제조 방법
KR20160054216A (ko) * 2014-11-06 2016-05-16 환인제약 주식회사 콜린알포세레이트를 함유하는 정제 및 그 제조방법
KR101794573B1 (ko) * 2016-11-22 2017-11-07 이니스트바이오제약(주) 콜린알포세레이트를 포함하는 속방출형 고형제제 및 이의 제조방법
EP3513782A1 (fr) * 2018-01-18 2019-07-24 Universita' Degli Studi Di Camerino Formulations de gel pour l'administration orale des medicaments, notamment à des patients souffrant de dysphagie

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