JPS58502097A - Expandable lattice of polyvinyl alcohol and polyethylene glycol - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Expandable lattice of polyvinyl alcohol and polyethylene glycol Summary of the invention Dosage forms for oral administration to patients of drugs, such as quinidine or propranolol I will provide a. The dosage form consists of a core containing the drug and a cover of an expandable lattice; The tonic lattice allows water to pass therethrough, causing dissolution of the drug and increasing the osmotic pressure. Under conditions, the expandable lattice expands to allow molecules of the drug to pass through it. Maintaining its structural integrity, when the dosage form comes into contact with the aqueous medium of the gastric dilator, the expansion Water is drawn into the core through the lattice - thereby creating an osmotic pressure; the expandable lattice expands in response, and the agent expands the resulting expanded lattice structure of the expandable lattice. It leaks through the structure.

In a preferred embodiment, the expandable lattice preferably has at least 75,000 Contains polyvinyl alcohol with a molecular weight. In a particularly preferred embodiment , the expandable lattice is made of polyvinyl alcohol having a molecular weight of about 75,000 to about 150,000. Contains alcohol. In another embodiment, the expandable lattice also has about 40 Contains polyethylene glycol having a molecular weight of 0 to about 4000.

Detailed description of the invention According to the present invention, there is provided a tablet coated with an expandable lattice that utilizes an osmotic pressure phenomenon. Ru. When the tablet is not subjected to osmotic pressure, the expandable lattice passes through the tablet. Give water passage to quinidine, propranolol or nitroglycerin Does not provide a drug outlet such as Tablets with prior art laser perforation or bursting Unlike sex tablets, the expandable lattice of the present invention will not burst or crack. do not have. Instead, the expandable lattice expands its lattice structure and dissolves when subjected to osmotic pressure. It consists of a homogeneous polymeric material that allows for the release of drugs. Check this mechanism for each This has been experimentally observed using large and small dye molecules of different colors. the larger one The dye molecules were polymerized and bonded to make them very large. Extended characteristics according to the invention The two different colors were coated inside the brat column using the air suspension coating method. If a tablet is formulated with a seed dye molecule, after placing such tablet in water, the small Only the color of the dying dye molecules can diffuse through the tablet's "skin" into the aqueous environment. was observed. That is, only the color of the smaller dye was observed. the larger one The lack of color of the polymerized dye molecules indicates that the expandable lattice was not ruptured. Ta.

In a preferred embodiment, polyvinyl alcohol and polyethylene glycol are used. Polymers based on LE (PEG) are provided as extensible lattices. polyvinyl The alcohol generally has a molecular weight greater than about 75,000, even more preferably 90,000 The maximum value depends on the ease of manufacturing of the polymer. Generally speaking, about 150,000 is the maximum value for practical use. Preferred specific example In this case, polyvinyl alcohol with a molecular weight of 115,000 is used.

The degree of hydrolysis should be relatively high. In a preferred embodiment, the degree of hydrolysis is Generally greater than about 90%, even more preferably at least 95%. experiment A degree of hydrolysis of approximately 98% has been found to be particularly suitable. polyethylene Glycols generally have a molecular weight of about 400 to about 4000 - even more preferably about 800 It has a molecular weight of ~1500. In the experiments conducted, a needle amount of 1000 was used. It was done.

The relative amounts of polyvinyl alcohol and polyethylene glycol are Depending on the desired properties, the warpage can be large. In one embodiment, it receives have a polymeric coating that maintains its structural integrity even during extreme osmotic pressures; is desired, polyvinyl alcohol is generally preferred over polyethylene glycol. A higher amount, preferably polyvinyl alcohol compared to polyethylene glycol. A weight ratio of about 9:1 is present. In other embodiments, faster release of the drug If at least partial erosion of the expanding lattice is desired due to A larger proportion of glycol is desirable. In one embodiment, polyethylene The glycol is present at about 20% by weight of the polyvinyl alcohol.

The total proportion of polyvinyl alcohol is generally about 5-20% by weight (the polymeric material (before drying), about 15% is a preferred embodiment. (This "wetting" calculation is based on sufficient Based on its maximum concentration in an aqueous medium that will allow the polymer to elongate and work. Shoes.

In specific cases where erosion of the polymer lattice is not desired, polyethylene glycol The amount is generally about 1710 of the weight of polyvinyl alcohol. For example, polyester Tylene glycol is generally present in an amount of about 0.1 to about 5% by weight. erosion is desired When present, the weight generally ranges from about 1% to about 10% polyethylene glycol. present invention With a polyvinyl alcohol content of 15% in the first example of A recall of about 1 to about 2% is preferred, and even more preferred for polyethylene glycols. approximately 1.5% by weight.

A lattice enhancer that promotes hydrogen bonding is preferably included in the polymer - triethanol. amines, sugars, citrates, tris-hydroxyaminomethane, phosphates, Urate salts and other hydrogen bond crosslinking agents are included. A preferred lattice enhancer is tris- Hydroxyaminomethane (Tris). Tris in an amount of about 0.1% to about 1% is particularly preferred. Appropriate for

For organic basic drugs, have an expandable lattice with pH adjustable properties. is preferred. Therefore, for such basic drugs, Tris and Trieta The pHII buffer compound itself, as exemplified by nolamine, can be used as a lattice enhancer. It is advantageous to do so. These basic lattice enhancers can also be used for non-basic drugs. If desired, the charge can be neutralized by using the salt form. . For example - for operating at neutral pH, Tris hydrochloride is preferred over Tris itself. Yes.

The amount of drug released from the polymer membrane along with the total amount desired for the period of release. It is defined taking into account the amount of Generally, the entire amount of drug is released in the gastrointestinal tract it is conceivable that.

The release rate depends not only on the choice of the polymeric coating components of the expansible lattice used in practice; It is also regulated by the amount and type of solid material inside the tablet, which affects the osmotic pressure; This osmotic pressure is the driving force in determining the rate of drug release. Pharmaceutically inert fraction The drug can advantageously be contained within the variably permeable membrane together with the drug.

Sugars such as sucrose can be used, or less soluble sugars such as lactose can be used As an example, lactose remains inside the membrane for a longer period of time than sucrose. the osmotic pressure aids in the extrusion of the drug from the variably permeable membrane. .

As an osmoattractant, mention may be made of methocel. cellulose and cells Any of the relatively water-insoluble but hygroscopic polymers such as loose derivatives It can be used in place of methocel. Other polymers containing hydration sites can also be used can. Sucrose is another preferred osmoattractant. Various sugars are sucrose It can be used instead of . The general requirement for sugar is that the sugar is released It should be of the same order of magnitude as the drug to be treated. sugar is bigger than drug It is also appropriate to that the sugar is substantially smaller than the drug to be released Usually not appropriate. This is because the mechanism of action of the expandable lattice is the penetration of the matrix. Expansion due to pressure expands to allow sugar to be released, but is also released. If the target drug is substantially larger than the sugar, the drug will remain. It is from. Therefore, when the lattice expands to allow sugar to be released, one drug also It is important to maintain conditions for release. The requirements for this to occur Always ensure that the sugar is the same size or larger than the drug, under certain conditions. There are things to do. Replace magnesium stearate with other suitable tablet lubricants be able to.

For example, pharmaceutical dosage forms for drugs such as propranolol can be used over a wide range of doses. You can arrange them.

25 to achieve the necessary therapeutic concentrations required for twice daily dosing. It is suggested to use doses of mg, 50■, 100■ and 1751n9/tablet. It is. For once-daily administration, a dosage form exactly twice the size mentioned above may be used. 50■, 100■, 200■ and 350m? with a dose of the The ejection movement is somewhat long.

Proprietary drugs such as quinidine, trinitroglycerin and theophylline Instead of lanolol, it can be administered by the oral dosage form of the present invention.

The following non-limiting examples serve to further explain the invention.

Example 1 Having a dosage form of quinidine disulfate that releases continuously over a 12 hour period is desired. This dosage form is taken twice a day. In one example The following is shown: Quinidine disulfate 300 per 1 soap, sucrose (granulated sugar per 91 tablets) ) 150 m91 tablet per Methocel (HydroxyPro Pill Methyl Cellulose) IQ Magnesium Stearate per Omfl tablet 5 ■ This formulation is used for normal tablet form, and it has a total of 555”! Compress into tablets with weight. Then, put this tablet in a suitable container such as Brat Column. coated with a gas phase coated column.

The coating materials used are: Polyvinyl alcohol 0 min-T' [115000) 9 parts polyethylene glycol (molecular weight 1000) 1 part. These two polymers are methanol-water Step 1: Dissolve in IV/V mixed solution. These polymers contained 5% polymer and 9% solvent. 5% (range polymer 5% to 10% dissolved in methanol-water mixture in two compositions) . Tablets were then prepared such that 5% of the total tablet weight was coating material (range 2-10%). ] Cover with this medium mixture in a grating force ram. Average coverage of 27.75 mL The material is added to each tablet and the current tablet weight is 555"? plus coating material 27 ．． Final set of tablets with a weight of 75 mL Tear V) - 582,75"ll',/tablet obtain a product. Tablets manufactured by the method presented here exhibit a release kinetics over a period of 12 hours. A total of 88% was released in 12 hours - giving almost zero-order movement.

Ki = Schiff (D) Generally used to facilitate sustained release ([ime] release) (Polymer film) It is desired to modify the pi-i constraints in the structure Sometimes. Tris (tris-hydroxyaminomethane) has the strength and desired p Can be used in small amounts (01-3% of polymer content) to promote H environment. The gas acts as both a pH buffer and a hydrogen bonding catalyst. Tris is three hides It has a roxy group and one amine group, so it is a hydrogen donor or hydrogen acceptor site. It is a molecule suitable for cross-linking. Similar coating systems can be used for various drug-containing tablets. Wear.

Example 2 Propranolol is a well-known and widely used drug for cardiac treatment. It is. The king's cardiac applications are against arrhythmia, angina and tachycardia. Also biased It is also used as a treatment for headaches. Propranolol is used for high blood pressure Ru. Other symptoms related to circulatory or cardiac problems may also be treated with propranolol. It can be treated with. Propranolol – it is generally symptomatic and prophylactic It is particularly indicated as a sustained release drug, as it is required for both targeted applications. Professional It is important to maintain therapeutic concentrations of the drug in the blood of patients who require pranolol. desired. A suitable time dosing system for oral administration of propranolol is 1 Twice a day - or, in the case of this drug, once a day. Pro plastic Norol has a biological half-life of 4 to 7 hours, requiring extremely narrow therapeutic blood concentrations. Propranolol can be administered on a once-a-day basis since it is not required. However, it is still possible to achieve adequate therapeutic concentrations in the patient's blood throughout the entire time. Ru.

In the following table, suitable for sustained release of propranolol for 24 hour treatment duration: The prescription is shown below.

Polyvinyl alcohol (molecule 1115000) 9 parts polyethylene glycol ( Molecule N 1000) 1 part These two components are mixed with methanol at a polymer content of 5-10%. Mix in water (1:IV/V). Using this as a coating material, air phase coating The device is applied to tablets made from propranolol-containing tablets.

The following table lists the ingredients of suitable tablets to be coated with this polymer film coating. Indicates: 100”? Propranolol 75 ~ Metcell (HPMC) 50m7 Sugar (sucrose, glucose, lactose etc.92ml Magnesium stearate The data in the above table is based on the film coating and the propranolol-containing tablets coated. to show the content. The tablet data shown above is 100m? For propranolol tablets and has a total weight of 227 ml. The surface for each sphere's volume is - the square of the radius. and varies by the third power, so of course - films for tablets of different sizes Some adjustment is required regarding the proportion of the coating. Maintains constant thickness of polymer coating In general, as the tablet size decreases, the film becomes more expensive. constitute a combination. In this case, we show an example of a film coating that is 10% of the total tablet weight. It is. 22.7 m'? A film coating of 22. is applied to each tablet. A weight increase of 7"9 occurs. The final tablet weight is 249.7 m9, and the coating Approximately 9% of the weight of the tablet was coated.

Membranes (polymer membranes) are used to facilitate sustained release of drugs, e.g. propranolol. It is desirable to modify the pH constraints in the film structure. Tris (Tori) (su-hydroxyaminomethane) strength and to promote the desired pH environment. It can be used in small amounts (from 0.1% to 3% of the polymer content. Tris can be used as a pH buffer and acts as both a hydrogen bonding catalyst and a hydrogen bonding catalyst. Tris has 3 hydroxy groups and 1 It has several amine groups, making it suitable for cross-linking of hydrogen donor or hydrogen acceptor sites. It is a child. Similar coating systems can be used for various drug-containing tablets.

Example 3 The oral pharmaceutical form of nitroglycerin is such that the nitroglycerin is configured to be emitted. This dosing system consists of regular Nidrog IJ serine-containing tablets. It is composed of a polymer film and is coated with a polymer coating to perform ejection motion. The tablet is milk 125 parts of ground sugar (10% trinitroglycerin), magnesium stearate 5 parts, 60 parts of sucrose and 40 parts of methocel. This trinitroglycerate Phosphorus: Film coatings for lactose systems are processed as follows. Final weight of this tablet is 252 ■. 20 m’i of polymer coating material per tablet: Polyvinyl alcohol (molecular weight 11.5000) 9 parts polyethylene glycol (Molecular weight 1000) Cover with 1 part. Therefore, the final tablet is 272”? The weight is 7.4% of the coating material. For the tablets obtained above, 9:1 Ratio of coating material polyvinyl alcohol and polyethylene glycol to methanol - Prepared in water at a concentration of 5%.

Mata, trinitroglycerin: Simply add the ground polyvinyl alcohol to the trinitroglycerin. Troglycerin: polyvinyl alcohol pulverized trinitroglycerin: lactose powder It can be used in the above formulation by replacing it with crushed material. trinitroglycerate Phosphorus: polyvinyl alcohol grind contains 10% nitroglycerin and 90% Composed of polymers. Polyvinyl alcohol polymers generally have a molecular weight of 10 000 88% hydrolyzed polyvinyl alcohol.

Membrane (pomer film) structure that facilitates sustained release of trinitroglycerin It may be desirable to modify the pH constraints within. Tris (Tris -hydroxyaminomethane) to promote strength and the desired pH environment. (01-3% of the polymer content). Tris is a pH buffer and hydrogen Acts as both a binding catalyst. Tris has three hydroxy groups and one amine is a molecule suitable for cross-linking of lever hydrogen donor or hydrogen acceptor sites with hydrogen groups. .

Similar coating systems can be used for various drug-containing tablets.

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Claims (1)

[Claims] 1. A film made of polyvinyl alcohol and polyethylene glycol. , of sufficient thickness to maintain its structural integrity when subjected to osmotic pressure, and Under the influence of osmotic pressure, it expands its lattice structure sufficiently so that drug molecules can pass through it. an expandable lattice structure that is thin enough to allow 2. The polyvinyl alcohol has a molecular weight of about 75,000 to about 150,000; Claims wherein said polyethylene glycol has a molecular weight of about 400 to about 4000. Structures in enclosure @1 term. (3) a drug-containing core and a coating of an expandable lattice through which water is allowed to flow. but under high pressure - conditions such that drug molecules can pass through it. The expandable lattice maintains its structural integrity and contacts the aqueous medium of the monogastric tract. water is then drawn into the space through the expandable lattice - thereby creating osmotic pressure. Expansion of the expandable lattice is caused by causing expansion of the expandable lattice according to the osmotic pressure. A dosage form for oral administration of drugs to patients that leaks the drug through a lattice structure. 4 Claims in which the drug is quinidine-propranolol or nitroglycerin Dosage forms according to paragraph 3. 5. The dosage form of claim 3, wherein said core contains an osmoattractant. 1