KR20160141044A - Extended Release Formulation for Oral Administration of Sildenafil - Google Patents
Extended Release Formulation for Oral Administration of Sildenafil Download PDFInfo
- Publication number
- KR20160141044A KR20160141044A KR1020150073883A KR20150073883A KR20160141044A KR 20160141044 A KR20160141044 A KR 20160141044A KR 1020150073883 A KR1020150073883 A KR 1020150073883A KR 20150073883 A KR20150073883 A KR 20150073883A KR 20160141044 A KR20160141044 A KR 20160141044A
- Authority
- KR
- South Korea
- Prior art keywords
- sildenafil
- active ingredient
- preparation
- controlled
- release oral
- Prior art date
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Classifications
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Abstract
Description
The present invention relates to a sildenafil controlled release oral preparation for the treatment of pulmonary arterial hypertension, and more particularly to a novel sildenafil controlled release oral preparation capable of reducing the number of daily administration.
Sildenafil is represented by the general formula (1) and is represented by the general formula (1): 1 - [[3- (6,7-dihydro- 1 -methyl-7-oxo- Yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine and its pharmaceutically acceptable salts are described in EP-A-0463756. Sildenafil is a selective inhibitor of the phosphodiesterase type-5 inhibitor (PDE-5 inhibitor) and is a drug that exhibits different uses depending on the dosage and dose. Sildenafil is marketed under the product name of Viagra (Pfizer) as a treatment for erectile dysfunction by taking 25 mg, 50 mg and 100 mg as sildenafil, and 20 mg as sildenafil once a day for three times a day for treatment of pulmonary arterial hypertension. It is marketed worldwide as TiO2 (Pfizer). It is mainly used for the improvement of athletic performance in pulmonary arterial hypertensive functional class II and III patients.
Sildenafil exhibits high solubility at low pH but low solubility at higher pH.
In addition, sildenafil has a half-life of about 4 hours, so it is taken three times a day.
This three times daily dose not only reduces the patient's adherence to the medication, but also loses the proper time for taking the medication, thus increasing the possibility of side effects. However, due to the pH-dependent solubility of the sildenafil drug, there have been many difficulties in developing a therapeutic agent for improving it.
A problem to be solved by the present invention is to provide a novel sildenafil controlled release oral preparation which can improve convenience of taking.
In addition, a problem to be solved by the present invention is to provide a method for producing a novel sildenafil controlled release oral preparation which can improve convenience of taking.
It is another object of the present invention to provide a method for treating pulmonary arterial hypertension by a novel sildenafil controlled release oral preparation.
Hereinafter, other problems not mentioned in the above-mentioned tasks will be clearly understood by those skilled in the art from the following description.
The present inventors have completed a novel oral preparation which can improve the convenience of administration by applying a sustained-release base suitable for sildenafil.
A sildenafil controlled-release oral formulation according to one embodiment of the present invention includes sildenafil, a pharmaceutically acceptable salt thereof, or a solvate thereof, and an active ingredient and a sustained release base.
The active ingredient may be sildenafil citrate.
The sustained-release base may be at least one selected from a hydrophilic polymer, a water-insoluble polymer, and a lipid material.
The hydrophilic polymer may be at least one selected from hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and carbomer.
Wherein the water-insoluble polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, poly (ethyl acrylate, methyl methacrylate) copolymer, and poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate) Or more.
The lipid material may be at least one selected from glyceryl behenate, glyceryl palmitostearate, glycerylolate, glyceryl stearate, and cetyl alcohol.
The sustained-release base may be contained in an amount of 50 to 1000 parts by weight based on 100 parts by weight of the active ingredient.
The sildenafil controlled release oral preparation may be a tablet.
The tablets may be either untreated or coated.
The sildenafil controlled-release oral preparation may be administered twice a day or once a day.
An example of a method for preparing a sildenafil controlled-release oral preparation according to an embodiment of the present invention includes preparing an active ingredient to prepare sildenafil, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient; The preparation of a slow release agent to prepare a slow release mechanism; And a formulation step of bringing the active ingredient prepared in the active ingredient preparation step into contact with the sustained release base material prepared in the sustained release base material preparation step so as to formulate a single preparation.
According to the present invention, it is possible to reduce the frequency of taking sildenafil, its pharmaceutically acceptable salt or solvate thereof, thereby improving the convenience of taking and improving the compliance with the medicament. In addition, it has the effect of reducing the incidence of side effects as well as increasing the therapeutic effect. In addition, the sildenafil controlled-release oral preparation can be effectively produced by the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS The advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below with reference to the accompanying drawings. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. To fully disclose the scope of the invention to those skilled in the art, and the present invention is only defined by the claims. Unless otherwise indicated throughout the specification, 'sildenafil' is meant to encompass sildenafil and its pharmaceutically acceptable salts, or solvates thereof, That is, sildenafil includes sildenafil hydrochloride, sildenafil maleate salt and the like, and solvate form including hydrate form such as sildenafil hydrate and the like, and sildenafil citrate is generally used, It is not limited.
[Chemical Formula 1]
&Quot; Controlled-release oral < / RTI > agent " means a controlled-release formulation of a pharmaceutical agent that is orally administrable to a mammal, including a human, as desired for the release of the active ingredient.
"Slow-release" means that the active ingredient is released slowly over a long period of time, for example in the form of a zero-order release, so that the efficacy can be maintained for a long period of time.
The 'sustained-release base' is a substance added to the preparation to release the preparation containing the active ingredient into the sustained release, and refers to a hydrophilic polymer, a water-insoluble polymer, a lipid material and the like depending on the solubility and characteristics of water.
The term 'hydrophilic polymer' refers to a pharmaceutical additive that dissolves in water or absorbs water to generate a viscosity, and is preferably, but not limited to, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, poly Vinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and carbomer.
By "water-insoluble polymer" is meant a pharmaceutical additive that is substantially insoluble in water, including but not limited to ethylcellulose, cellulose acetate, poly (ethyl acrylate, methyl methacrylate) Ethyl acrylate, methyl methacrylate, trimethyl ammonium ethyl methacrylate) copolymer.
"Lipid substance" means a substance having a property of not mixing with water, such as glyceryl behenate, glyceryl palmitostearate, glyceryl alcoholate, glyceryl stearate, cetyl alcohol, etc., .
Hereinafter, the present invention will be described in more detail.
A sildenafil controlled release oral formulation according to an embodiment of the present invention comprises an active ingredient that is sildenafil, a pharmaceutically acceptable salt thereof, or a solvate thereof, and preferably also contains a sustained-release base so that the pH-dependent solubility Sildenafil with a sustained-release system is capable of sustained release. At this time, by applying at least one selected from the hydrophilic polymer, the water-insoluble polymer, and the lipid material to the sustained-release base material, the desired sustained release pattern can be obtained by avoiding the lowering of the solubility of the sildenafil, So that emission control becomes possible.
The sustained-release base may contain 50 to 1000 parts by weight of the active ingredient. If it is less than the above range, it may be difficult to exhibit a sustained release pattern. If the above range is exceeded, the release may be delayed excessively, so that the active ingredient may be lost without being absorbed.
Since the sustained release of sildenafil is possible due to the above-described structure, the sildenafil-controlled-release oral preparation according to one embodiment of the present invention can reduce the number of doses, preferably once a day or once a day Can be used.
In order to enable administration twice a day or once a day, preferably, the sildenafil controlled release oral preparation according to one embodiment of the present invention contains the active ingredient and the sustained release base so as to exhibit sustained release can do. That is, by bringing the active ingredient into contact with the sustained-release base and formulating it in a single preparation, sustained release can be achieved. At this time, the sildenafil controlled-release oral preparation may be a tablet. The tablets may be tablets or coated tablets, and the like.
The sildenafil controlled release oral preparation can be formulated into various formulations such as powders, granules, tablets, pellets, capsules, and kits.
The active ingredient contained in the sildenafil controlled-release oral preparation may vary depending on the patient's body weight, age, sex, and symptoms. In general, sildenafil may be administered in an amount of 20.0 mg per day as an adult. In the past, the present invention was administered three times a day, but the present invention enabled the administration twice a day or once a day, thereby increasing convenience of medication. That is, the method for treating pulmonary arterial hypertension according to an embodiment of the present invention is a method for treating pulmonary arterial hypertension by administering to a mammal including a human, which requires administration of the novel sildenafil controlled- It is possible to treat hypertension diseases, and it is possible to improve convenience of taking and improve compliance of medication. In addition, it has the effect of reducing the incidence of side effects as well as increasing the therapeutic effect. Mammals, including humans, in need of such administration refer to those suffering from pulmonary arterial hypertension and the like.
Such sildenafil controlled release oral preparations may be administered alone or in combination with other pharmaceutically acceptable carriers, excipients, disintegrants, surfactants, solubilizers, lubricants, dispersants, buffer solutions, preservatives, flavors, Can be incorporated and formulated.
That is, it can be formulated into suitable forms using pharmaceutically suitable and physiologically acceptable excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants, perfumes and the like.
Examples of disintegrants include starch glycolic acid sodium, corn starch, potato starch, pregelatinized starch, bentonite, montmorillonite, veegum, microcrystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, or But are not limited to, alginic acid, croscarmellose sodium, crospovidone, sodium bicarbonate, citric acid, etc., alone or in combination.
Further, it may further include a binding agent for improving the granulation qualities and the dissolution rate of the tablet. Examples of the binder include microcrystalline cellulose, gelatin, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone (povidone), polyvinyl alcohol, copovidone, pregelatinized starch, starch, hydroxypropylcellulose And hydroxypropylmethylcellulose, but are not limited thereto.
It may further comprise a diluent. Examples of the diluent include, but are not limited to, starch, microcrystalline cellulose, lactose, glucose, mannitol, alkaline earth metal salts, clay, polyethylene glycol and dicalcium phosphate.
It may further comprise a lubricant. Examples of the lubricant include lubricants such as talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, hydrogenated vegetable oil, polyethylene glycol, glyceryl behenate, Glyceryl monostearate, and the like may be used, but the present invention is not limited thereto.
In addition, it is also possible to selectively add a solubilizing agent such as an emulsifier such as sodium lauryl sulfate, poloxamer, polysorbate and sorbitan derivatives, a surfactant, polyethylene glycol, a medium chain triglyceride, an isopropyl derivative and a pyrrolidone derivative .
Also, the components that can be included include antioxidants, colorants, flavors, preservatives, and sweeteners.
The method for preparing a sildenafil controlled-release oral preparation comprises the steps of preparing an active ingredient to prepare sildenafil, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient; The preparation of a slow release agent to prepare a slow release mechanism; And a formulation step of bringing the active ingredient prepared in the active ingredient preparation step into contact with the sustained release base prepared in the preparation of the sustained-release base so as to formulate a single preparation, thereby preparing a sildenafil controlled release oral preparation.
The preparation of the granules in the formulation may be carried out by mixing the components directly, by pressing them with a roller, or by a method such as wet-granulation, melt-granulated, melt congealed, can do.
In addition, the preparations of the present invention can be prepared by any suitable method in the art, for example Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.
The matters mentioned in the above-mentioned sildenafil controlled release oral preparations and those mentioned in the above-mentioned methods for preparing sildenafil controlled release oral preparations are applied as long as they are not mutually contradictory.
Hereinafter, the present invention will be described in more detail with reference to Examples 1 to 4 and Experimental Example 1. The compounds used in the following Examples and Experimental Examples were the highest available in the market. Unless otherwise noted, the ingredients listed in the Handbook of Pharmaceutical Excipient were purchased and used.
< Example 1> Sildenafil Controlled Release Oral Formulation ( Monolayer ) Produce
1,000 T portions were prepared in the composition and content described in Example 1 of Table 1. Sildenafil citrate, mannitol, and colloidal silicon dioxide were sieved through a No. 20 sieve and mixed for 10 minutes. Separately, polyvinylpyrrolidone is dissolved in purified water to prepare a binding solution, which is then fed to the mixture. Coalesced granules are dried in a fluid bed dryer (SFC-lab, Freund, Japan) so that the moisture content is less than 3%. Dry the granules with a No. 20 sieve. To the above-mentioned sieved product, a 35-sieved sieved hypromellose is added and mixed for 30 minutes. When mixing was completed, magnesium stearate sieved through a No. 35 sieve was added and mixed for 3 minutes to prepare sustained release granules. A 15.5 mm long rectangular punch was mounted on a rotary tablet machine (ZPS-8, China) and tabletted to prepare tablets. Separately, OPA DRY 03B44115 (Curcorcon, Korea) was dissolved in a purified water-ethanol mixed solution to prepare a coating solution. The tablets thus completed were placed in a coater (SFC-30F, Korea) and coated with a coating solution to complete the preparation.
< Example 2> Sildenafil Controlled Release Oral Preparation ( Monolayer ) Produce
The procedure of Example 1 was repeated except that polyethylene oxide was used instead of hypromellose as the composition and content of Example 2 of Table 1. [
< Example 3> Sildenafil Controlled Release Oral Preparation ( Monolayer ) Produce
The composition and content of Example 3 in Table 1 were prepared in the same manner as in Example 1, except that hypromellose and polyethylene oxide were used at the same time in place of using hypromellose alone.
< Example 4> Sildenafil Controlled Release Oral Formulation ( Monolayer ) Produce
The same procedure as in Example 1 was repeated, except that the dosage form of sildenafil citrate was increased so that the dosage form could be administered once a day as in the composition and content of Example 4 in Table 1.
(100,000 mPas)
< Comparative Example 1> Sildenafil Rapid emissivity Oral preparation ( Monolayer ) Produce
The composition and content of Comparative Example 1 in Table 1 were prepared in the same manner as in Example 1 except that no hypromellose was used.
< Experimental Example 1> Dissolution Test Results
The sildenafil controlled release oral preparation prepared in Example 1 and the sildenafil prepared in Comparative Example 1 were tested according to the following dissolution test conditions and the results are shown in Table 2 below.
≪ Dissolution test conditions >
Dissolution Test Method: Dissolution Test Method 2 (paddle method) of General Test Methods of the Korean Pharmacopoeia
Paddle speed: 50 rpm
Eluent: First solution (pH 1.2) of Korea Pharmacopoeia Disintegration Test Method 900 ml
Sample collection time: 60, 120, 240, 360, 480, 720 minutes
As shown in Table 5, it was confirmed that the sildenafil-releasing preparation of Comparative Example 1 completed the elution within 1 hour but the sildenafil sustained release preparation gradually released until 12 hours.
As described above, the preparation of the present invention not only increases the patient's compliance with the medication by decreasing the number of doses by extending the blood half-life and maximum blood concentration time of the drug through the sustained-release of the active ingredient, It can be seen that the possibility of side effects that may occur as a result of missing a proper dosing time can be further reduced.
That is, by developing a novel controlled-release oral preparation that exhibits a 24-hour effect twice a day or once daily, the present invention provides a novel therapeutic agent for pulmonary arterial hypertension , Increased therapeutic efficacy, and reduced incidence of side effects, as well as a new method of treating pulmonary arterial hypertension through sildenafil.
As a result, it can be seen that the present invention provides a novel oral preparation, a preparation method thereof, and a therapeutic method, which can improve convenience of use by applying a sustained-release base suitable for pH-dependent solubility characteristics of sildenafil.
Claims (10)
Wherein the active ingredient is sildenafil citrate.
Wherein the slow release base is at least one selected from a hydrophilic polymer, a water-insoluble polymer, and a lipid material.
Wherein the hydrophilic polymer is at least one selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and carbomer.
Wherein the water-insoluble polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, poly (ethyl acrylate, methyl methacrylate) copolymer, and poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate) Sildenafil controlled release oral dosage forms.
Wherein the lipid material is at least one selected from glyceryl behenate, glyceryl palmitostearate, glycerylolate, glyceryl stearate, and cetyl alcohol.
Wherein the slow release base is contained in an amount of 50 to 1000 parts by weight based on 100 parts by weight of the active ingredient.
Wherein the sildenafil controlled-release oral preparation is a tablet.
Wherein the sildenafil controlled release oral preparation is administered twice a day.
The preparation of a slow release agent to prepare a slow release mechanism; And
Wherein the active ingredient prepared in said active ingredient preparation step is contacted with the sustained release base prepared in said sustained release base preparation step to formulate a single formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150073883A KR20160141044A (en) | 2015-05-27 | 2015-05-27 | Extended Release Formulation for Oral Administration of Sildenafil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150073883A KR20160141044A (en) | 2015-05-27 | 2015-05-27 | Extended Release Formulation for Oral Administration of Sildenafil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20160141044A true KR20160141044A (en) | 2016-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020150073883A KR20160141044A (en) | 2015-05-27 | 2015-05-27 | Extended Release Formulation for Oral Administration of Sildenafil |
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| Country | Link |
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| KR (1) | KR20160141044A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180083239A (en) * | 2017-01-12 | 2018-07-20 | (주) 넥스팜코리아 | Oral composition of sustained-release formular containing limaprost or limaprost alfadex |
-
2015
- 2015-05-27 KR KR1020150073883A patent/KR20160141044A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180083239A (en) * | 2017-01-12 | 2018-07-20 | (주) 넥스팜코리아 | Oral composition of sustained-release formular containing limaprost or limaprost alfadex |
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