• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    The disclosed subject matter relates to a novel drug delivery system comprising a drug formulation and a means for releasing the drug formulation from the delivery system.
    公开号:KR20000005230A
    申请号:KR1019980707917
    申请日:1997-03-20
    公开日:2000-01-25
    发明作者:아털 데브다트 아이어；앤드류 램；쥬디 에이. 매그루더；로렌스 지이. 함멜；패트릭 에스. 엘. 웅
    申请人:에드워드 엘.멘델；앨자 코포레이션；
    IPC主号:
    专利说明:

    Uniform Drug Delivery Therapy
    There is an absolute need for formulations suitable for controlled uniform administration of a medicament for the purpose of treatment. To date, in pharmacy and medicine, medicaments are administered in the form of tablets or capsules, which are conventional formulations. These conventional formulations do not deliver the medication evenly because it delivers the medication all at once, and the content of the medication in the blood becomes uneven, characterized by peaks and bones, which can be adjusted over a long period of time and cannot provide uniform treatment. . The prior literature provides formulations for continuous treatment. For example, U.S. Patent Nos. 4,327,725 by Cortes and Tueuwes and U.S. Patent Nos. 4,612,008 by Wong, Barclay, Deeters, and Theeuwes. 4,765,989 and 4,783,337 disclose formulations that provide treatment by generating osmotic pressure within the formulation. The formulations of these patents successfully deliver a medicament for the desired treatment. However, in delivering some medications, these formulations often exhibit strange drug release rate patterns, such as non-uniform changes in drug release rates, and the formulations may intermittently stop working, i.e. stop drug delivery. .
    It is clear that there is an urgent need for a reliable formulation as seen above. There is a need for formulations that can deliver medicaments for long periods of time at substantially uniform rates. There is also a need for a formulation that is substantially free of release rate profiles that can deliver the required amount of drug while reducing the amount of drug remaining in the formulation at the end of drug delivery. It will be appreciated that the formulations of the present invention, novel and unexpected by those skilled in the art of drug delivery, have been made possible by providing substantially uniform and known drug-release profiles and by solving the problems of the prior art. In addition, such formulations represent a significant improvement and significant contribution in the field of pharmaceutical delivery.
    The present invention relates to formulations that can deliver a medicament for a long period of time at a substantially uniform rate. More specifically, the present invention relates to formulations that can provide a pattern for releasing a medicament at a known constant rate suitable for the desired treatment. The present invention is directed to formulations that are capable of delivering a uniform, constant, controlled dose of a single dose of a medicament over a long period of time.
    1 shows the change in drug release rate when a polymer having at least 25% of particles larger than 250 μm is present and the size of the drug particles is between 1 and 900 μm.
    2 shows the change in drug release rate released from the formulation when 25% of the polymer having particles larger than 250 μm is present and the size of the drug particles is less than 150 μm.
    FIG. 3 shows a marked reduction in the change in drug release rate for formulations comprising a medicament with particles less than 150 μm and a polymer with particles less than 250 μm.
    <Object of the Invention>
    Thus, as seen above, it is a direct object of the present invention to provide formulations that deliver for extended drug delivery treatment periods at substantially uniform dosages to sites that will absorb the biological agent.
    It is yet another object of the present invention to provide novel formulations which exhibit substantially the same dosage and release rate over a long period of time substantially avoiding administering the medicament at a heterogeneous and varying rate.
    It is a further object of the present invention to provide a formulation which delivers a predetermined dose for a long time in the same way while reducing the amount of medicament remaining unreleased in the formulation.
    Still another object of the present invention comprises pharmaceutical particles between 5 μm and 150 μm and hydrophilic polymer particles between 5 μm and 250 μm, wherein the drug particles and hydrophilic polymer particles work together to provide a uniform, unchanging release rate, ie substantially To provide a pharmaceutical composition characterized in that it provides a release rate for a long time without variation and substantially no reduction.
    Another object of the present invention is a group consisting of a drilled exit, a bioerosion exit, a leaching exit, a solubilizing exit and an outlet formed by rupture. To provide a formulation comprising a membrane surrounding a pharmaceutical core comprising pharmaceutical particles of 1 μm to 150 μm and hydrophilic polymer particles of 1 μm to 250 μm delivered together from the formulation through an outlet formed by a method selected from.
    Another object of the present invention is to absorb and hydrate a fluid and a membrane comprising a semipermeable composition surrounding a core comprising a pharmaceutical layer comprising a pharmaceutical particle comprising 1 μm to 150 μm and hydrophilic polymer particles 1 μm to 250 μm. Inflate the volume of the drug layer into the orifice, the passageway, the pores, the microporous channels, the porous overlay, the porous insert, the micropore, the small It is to provide a formulation comprising a substitution layer comprising an osmopolymer-hydrogel for substitution through a membrane outlet selected from the group consisting of pore membranes and porepassageways.
    Another object of the present invention is to select drug particles from 1 μm to 150 μm, to select hydrophilic polymer particles from 1 μm to 250 μm, to mix the selected particles into a drug-polymer core, and to add up to 30 agents to the drug A method for delivering a medicament capable of delivering a drug at a substantially uniform and substantially rate from a formulation comprising surrounding the core with a membrane comprising a means for delivering at a substantially uniform and release rate for a long time to time. To make it possible.
    Still another object of the present invention is to absorb a fluid, a pharmaceutical composition comprising 0.05ng to 1.2g of a drug having a particle size of 1 μm to 150 μm and a hydrophilic polymer having a particle size of 1 μm to 250 μm for delivering a drug to a human body, A propellant composition that swells and pushes the pharmaceutical composition out of the formulation, a wall surrounding the drug and the propellant composition and positioned between the inner surface of the wall to control the absorption of fluid into the drug and the propellant composition for between 30 minutes and 4 hours And an inner coating layer surrounding the propellant composition, and one or more outlet means inside the wall capable of delivering the pharmaceutical composition for a long time at a uniform and unchanging rate.
    Other objects, features and advantages of the present invention will become more apparent in the pharmaceutical release industry, including pharmaceuticals and medicines, from the description and claims below.
    Detailed Description of the Invention
    The following examples illustrate the invention, and these examples and their equivalents will become apparent to those skilled in the pharmaceutical release arts with reference to the specification or claims of the invention and for any reason they limit the invention. It should not be considered to be.
    <Example 1>
    Formulations for oral delivery of the drug to the gastrointestinal tract of patients in need of drug treatment are prepared as follows: First, 5 mg of amlodipine besylate, a 135 μm calcium channel blocker, is injected into a fluid bed processor. ) Is mixed with a 5% solution of poly (vinylpyrrolidone) having a number average molecular weight of 30,000 available from General Aniin and New York, NY. The granulated product was then purchased from Union Carbide, Denver, Connecticut, 7.5 mg of poly (alkylene oxide) or poly (ethylene oxide) with a mean molecular weight of 175,000 and a particle size of 235 μm, 0.5 mg of sodium chloride. And 0.02 mg stearic acid and mix for 7 minutes at 35 rpm to obtain a homogeneous mixture. The homogeneous mixture is compressed into a pharmaceutical composition and enclosed by a wall containing a semipermeable composition and a therapeutic agent forming an outlet.
    The wall composition comprises 65% by weight of cellulose acetate having a number average molecular weight of 30,000 and an acetyl content of 34% dissolved in acetone: water. To this is added 1.8% by weight of triacetin and 1.5% by weight of sodium chloride with constant stirring. The pharmaceutical composition is sprayed in a fluid bed air flotation coater to produce 10% by weight of walls. The formulation is dried at 25 ° C. for 18 hours. The formulation releases amlodipine besylate through a microchannel made by solution leaching of sodium chloride from the gastrointestinal fluid of the patient at an unchanging rate.
    <Example 2>
    Example 2 shows that the drug is 5 mg of lisinopril known as an angiotensin converting enzyme inhibitor, 10 mg of buspirone hydrochloride known as an anxiety agent and oxybutynin hydro known as a relief of bladder instability. Example 1 is followed intact, except that it is selected from the group consisting of 5 mg of oxybutynin hydrochloride, the lubricant is magnesium stearate and the semipermeable wall contains mannitol.
    <Example 3>
    Formulations capable of osmotically and hydrodynamically controlled release of an effective drug are prepared as follows: First, 500 mg of oral antimicrobial ciprofloxacin hydrochloride with 125 μm in a mixing vessel is added and the particle size is 135 microns and the number average 105 mg of carboxymethylcellulose sodium having a molecular weight of 22,000 is added and the components are mixed for 3 to 5 minutes to form a homogeneous mixture. Next, 10 mg of 88 microcrystalline cellulose having a number average molecular weight of 11,000 was added to the mixing vessel, and 0.05 mg of sodium lauryl sulfate, a drug delivery surfactant, was added to mix all the components for 5 minutes. An aqueous solution containing 7.5 mg of poly (vinylpyrrolidone) having a number average molecular weight of 30,000 is then added with mixing, and the resulting mixture is passed through an extruder, placed in a small tray, and dried overnight. The granules are dried at 50 ° C. for 5 hours and 0.03 mg of lubricant is added for 1 minute with mixing. The solid fluid absorbing osmotic care is prepared in a tablet by pressing with a concave punch.
    Next, 94% by weight of hydroxyethyl cellulose having a number average molecular weight of 90,000 and 6% by weight of polyethylene glycol are contained in distilled water, and the skin is encircled around the pharmaceutical composition with an inner subcoat containing no drug. The pharmaceutical composition was dried at 45 ° C. for 1 hour. Thereafter, cellulose acetate having an acetyl content of 39.43% was added to a co-solvent of methylene chloride and methanol, followed by stirring and heating to form an envelope including a semipermeable composition and a pore-channel forming group. Then, sorbitol having pore-forming ability was added to the cosolvent of water and methanol, and polyethylene glycol was added to prepare an outer coating solution. Finally, the outer coating solution was coated around the skin in a pan coater and dried at 45 ° C. for 18 hours in a forced air oven to obtain the required formulation. In operation in the gastrointestinal fluid of the human body in need of drug treatment, the formulation is uniform in the release of the drug through the adjustable pore outlet passageway, made by the fluid leaching of soluble pore forming additives bound to the semipermeable sheath. And provide unchanged speed. The cooperation of the drug particles with the hydrophilic polymer particles provides a viscous gel that pushes the drug through the outlet at a given rate.
    <Example 4>
    The drug is simvastatin 40 mg for lowering cholesterol, venlafaxin 75 mg for antidepressants, 20 mg for fluoxetine for antidepressants, 20 mg for nifedipine for antidepressants, and lovastatin for lowering cholesterol. 40 mg, engiotensin converting enzyme inhibitor maleic acid enalopril maleate, 20 mg, diltiazem 120 mg, which regulates calcium ion influx, ciprofloxacin hydrochloride 500 mg, Oral antidepressant sertratine hydrochloride 100 mg, immunosuppressant cyclosporin 100 mg, alpha-adrenoceptor blocker terazosin hydrochloride 1 mg, 5-hydroxytryptamine receptor 50 mg of succinic acid sumatriptan, 40 mg of sodium hypovastatin travastatin, nelfinavir, saqui Anti-HIV-proteinase inhibitors such as saquinavir, indinavir or ritonavir, anti-HIV, lobbies such as zidovudine, didanosine or lamivudine Reverse transcriptase inhibitors such as loviride, antiviral herpes 500 mg, such as fumciclovir or gancidovir, 10 mg sodium alendronate for the treatment of osteoporosis and menopause, infertitis and bone Example 3 is followed except that it is selected from the group consisting of 2.5 mg of conjugated estrogen known as a therapeutic agent for vascular dyskinesia associated with osteoporosis related to loss of weight.
    Example 5
    Formulations that release the drug at oral uniform and unchanged rates into the biological drug receptor are prepared as follows: First, verapamil, which exhibits an uneven particle distribution with a particle size of 1 to 900 microns, suitable for treating angina and hypertension. 6,000 g of hydrochloride, 3,047 g of poly (ethylene oxide) having a number average molecular weight of 300,000 and 25% of particles larger than 250 microns, 500 g of sodium chloride and 100 g of poly (vinylpyrrolidone) having a number average molecular weight of 40,000 are fluid bed granulators. It was added to a Freund Flo-Coater's bowl. The vessel is attached to the flow-coating machine and the granulation process begins. The dried powder is then air-lifted and mixed for 5 minutes. Then, a solution prepared by dissolving 300 g of poly (vinylpyrrolidone) having a number average molecular weight of 40,000 in 4,500 g of water is dispersed in the powder phase through two nozzles. The coating conditions were monitored during the dispersion of the poly (vinylpyrrolidone) solution and the results were as follows: the total dispersion rate at each nozzle was 240 g / min, the inlet temperature was 45 ° C. and the air inflow was 1,000 cfm. The coating process is computerized and automated during the cycle. Each cycle involves 30 seconds of solution dispersion, 2 seconds of drying, and 10 seconds of agitation of the filter bag to remove possible powder precipitates. By the end of the dispersion of the solution the coated granulated particles are allowed to continue for 25 minutes in the drying process. Power off the machine and remove the coated granules from the coater. The coated granules are made to a specific size using a flowing air mill. The granules were transferred to a mixer, mixed, smoothed with 50 g of magnesium stearate, and mixed with 4 g of butylated hydroxytoluene to prepare a pharmaceutical composition.
    Next, the propellant-substituted composition is prepared as follows: First, 7,342 g of poly (ethylene oxide) having a number average molecular weight of 7 million, 2,000 g of sodium chloride, 200 g of hydroxypropylmethylcellulose having a number average molecular weight of 11,200 and black oxidation 100 g of ferric iron was added to a Freund Flo-Coater's bowl. The vessel was attached to the flow-coating machine and the granulation process started to produce this process. The dried powder was air floated and mixed for 6 minutes. Then, a solution prepared by dissolving 300 g of hydroxypropylmethylcellulose having a number average molecular weight of 11,200 in 4,500 g of water is dispersed in an air-lifted powder mixture through two nozzles. The coating conditions were monitored while the hydroxypropylmethylcellulose solution was dispersed. The coating conditions are the same as in the pharmaceutical granulation step except for the drying step of less than 25 minutes. The granulated powder is removed from the granulator to a specific size using a flowing air mill. The granules were transferred to a mixer, mixed, smoothed with 50 g of magnesium stearate, and 8 g of butylated hydroxytoluene were mixed to prepare a pro-substitution composition.
    The pharmaceutical composition and the propellant composition were then compressed to make a bilayer core. First, 300 mg of the pharmaceutical composition comprising 180 mg of verapamil hydrochloride was added to a punch and compacted, and 100 mg of the propellant composition was added to the punch and pressed at a pressure of 2,200 pounds to contact a diameter of 13/32 inch (1.032 cm). Bilayer arrays were prepared.
    Next, the bilayer core was coated with skin. The skin contains 95% hydroxyethylcellulose with a number average molecular weight of 90,000 and 5% polyethylene glycol with a number average molecular weight of 3,350. The components are dissolved in water to form a 5% solid solution. The skin-forming composition was dispersed around the bilayer core in a 24-inch Vector Hi-Coater. Dried skin is 79 mg.
    Next, the hydroxyalkyl cellulose, hydroxyethyl cellulose and the skinned bilayer core were again coated with the semipermeable composition. A composition forming a protective coating film comprising 60% of cellulose acetate having an acetyl content of 39.8%, 35% of hydroxypropylcellulose having a number average molecular weight of 40,000 and 5% of polyethylene glycol having a number average molecular weight of 3,350 was prepared using methylene chloride: methanol (90 : 10 weight: weight) 4% of a solid solution was prepared by dissolving in a cosolvent. The semipermeable film forming composition was dispersed around the skinned bilayer core. The semipermeable membrane is 43 mg after drying.
    Two 27 mil (0.686 mm) outlet passages were then drilled through the outer semipermeable membrane and the inner sheath layer to connect the drug layer with the outside of the formulation. Drying was carried out at 50 ° C. and 50% humidity for 96 hours to remove residual solvent. Finally, the formulation was dried at 50 ° C. for 2 hours to remove excess moisture.
    Formulations made for this method were 180 mg of verapamil hydrochloride, 91.41 mg of poly (ethylene oxide) with a molecular weight of 300,000, 12 mg of poly (vinylpyrrolidone) with a molecular weight of 40,000, sodium chloride 15 mg, butylated hydroxytoluene 0.12 A pharmaceutical composition comprising 300 mg of magnesium and 1.5 mg of magnesium stearate. The 100 mg propellant-substituted composition contains 73.5 mg of poly (ethylene oxide) having a molecular weight of 7,000,000, 20 mg of sodium chloride, 5 mg of hydroxypropylmethylcellulose having a molecular weight of 11,200, 0.92 mg of black ferric oxide, and butylated hydroxytoluene. 0.08 mg and 0.5 mg magnesium stearate. The skin of the formulation of 78.8 mg consists of 74.86 mg of hydroxyethyl cellulose having a molecular weight of 90,000 and 3.94 mg of polyethylene glycol having a molecular weight of 3,350. The outer wall of 42.6 mg consists of 25.56 mg of cellulose acetate having an acetyl content of 39.8%, 14.90 mg of hydroxypropyl cellulose having a molecular weight of 40,000, and 2.13 mg of polyethylene glycol having a molecular weight of 3,350. The mean release rate (dm / dt) t of this formulation was 18.6 mg / hr between 4 and 9 hours.
    The delivery pattern of the formulations made by these examples is illustrated in FIG. 1. In FIG. 1 the non-uniform and varying release rates are shown above the floats, indicated by lines extending from zero to the right of the figure. The release rate change is the value for a medicament in which the particle size is from 1 to 900 microns in the presence of a polymer having at least 25% of particles larger than 250 microns. The solid line represents the percentage of deviation from the overall average release rate. The average release rate of each formulation was indicated numerically along the solid line starting at zero. The variation in Figure 1 is due to the lack of a uniform range of uniform particles in the formulation. The showing of deviations is characterized by the substantial deviation of each system from the average release rate of the formulation at steady state. This variation is due to the lack of ability to deliver and support large drug particles, such as verapamil hydrochloride of the hydrophilic polymer poly (ethylene oxide), the difference in hydration time between large drug particles and small drug particles, and Occurs due to large hydrophilic polymers of 250 μm or more, which significantly change the hydration and drug flotation properties, resulting in a negative variation with a large percentage in (dm / dt) i compared to (dm / dt) t . (dm / dt) t represents the total mean release rate of all formulations when the deviation is zero, (dm / dt) i represents the average release rate at 4 to 9 hours of each formulation, and (% dev) i Represents the percentage of mean release rate deviation of each formulation (from 4 to 9 hours) relative to the overall mean release rate. The numerical values shown in the figure are obtained from the following equations.
    (% Deviation) = [(dm / dt) i- (dm / dt) t ] / (dm / dt) t
    <Example 6>
    Formulations for oral delivery of a medicament to the human body are prepared as follows: First, 6,000 g of verapamil hydrochloride with a particle size less than 150 microns, poly with a number average molecular weight of 300,000 and 25% of particles larger than 250 μm. 3,047 g (ethylene oxide), 500 g sodium chloride and 100 g poly (vinylpyrrolidone) having a number average molecular weight of 40,000 were added to the fluid bed granulator vessel. Granulation was performed for 7-10 minutes. The dried powder was then air-lifted and mixed for 5 minutes. Then, a solution prepared by dissolving 300 g of poly (vinylpyrrolidone) having a number average molecular weight of 40,000 in 4,500 g of distilled water was dispersed on the dried powder through two nozzles. The coating conditions were monitored during the dispersion and the results were as follows: the total dispersion rate at each nozzle was 240 g / min, the inlet temperature was 45 ° C. and the air inflow was 1,000 cfm. The coating process is automated while cycling. Each cycle includes 30 seconds of solution dispersion, 2 seconds of drying, and 10 seconds of stirring the filter bag to remove possible powder precipitates. By the end of the dispersion of the solution the coated granulated particles are allowed to continue for 25 minutes in the drying process. Power off the machine and remove the coated granules from the coater. The coated granules are made to a specific size using a flowing air mill. The granules were transferred to a mixer, mixed, smoothed with 50 g of magnesium stearate, and mixed with 4 g of butylated hydroxytoluene to prepare a pharmaceutical composition used to form a layer in the bilayer core.
    Next, the propellant composition was prepared as follows: First, 7,342 g of poly (ethylene oxide) having a number average molecular weight of 7,000,000, 2,000 g of sodium chloride, 200 g of hydroxypropylmethylcellulose having a number average molecular weight of 11,200 and a black oxide second 100 g of iron was added to the vessel of the fluid bed granulator. The granulation process was started and the dried powder was air floated and mixed for 6 minutes. Then, a solution prepared by dissolving 300 g of hydroxypropylmethylcellulose having a number average molecular weight of 11,200 in 4,500 g of water is dispersed on an air-lifted powder mixture. The coating state was monitored during the dispersion. Physical conditions are the same as in the pharmaceutical granulation step, except that it has a drying step of less than 25 minutes. The granulated powder is removed from the granulator to a specific size using a flowing air mill. The granules were transferred to a mixer, mixed, smoothed with 50 g of magnesium stearate, and 8 g of butylated hydroxytoluene were mixed to prepare a propellant composition.
    The pharmaceutical composition and the propellant composition were then compressed to make a bilayer core having a layer with a contact arrangement. First, 400 mg of the pharmaceutical composition comprising 240 mg of verapamil hydrochloride was added to a tablet punch to be compacted, and 135 mg of the propellant composition was added to the punch and pressed at a pressure of 2,300 pounds to make a 7/16 inch (1.11 cm) diameter contact. A double layer was prepared.
    Bilayer core tablets were coated with skin. The skin contains 95% hydroxyalkylcellulose with a number average molecular weight of 90,000 and 5% polyethylene glycol with a number average molecular weight of 3,350. The components are dissolved in water to give 5% solid solution. The composition that forms the skin is dispersed around the bilayer core in a coater. Dried skin was 93 mg.
    Next, an envelope was applied to the formulation. Sheathed bilayer cores were coated with semipermeable membrane walls. The film-forming composition comprises 60% cellulose acetate with an acetyl content of 39.8%, 35% hydroxypropylcellulose with a number average molecular weight of 40,000 and 5% polyethylene glycol with a number average molecular weight of 3,350. The composition forming the film was dissolved in a methylene chloride: methanol (90:10 weight: weight) cosolvent to prepare 4% of a solid solution. The semipermeable membrane wall forming composition was dispersed around the bilayer core skinned in the coater to obtain a double coated formulation. The semipermeable membrane was 51 mg after drying.
    Then, two 27 mil (0.686 mm) outlet passages through the outer and inner coating layers were drilled to connect the drug layer and the outside of the formulation. Drying was carried out at 50 ° C. and 50% humidity for 96 hours to remove residual solvent. Finally, the osmotic formulation was dried at 50 ° C. for 2 hours to remove excess moisture.
    Formulations made for this method were 240 mg of verapamil hydrochloride, 121.88 mg of polyethylene oxide with a molecular weight of 300,000, 16 mg of poly (vinylpyrrolidone) with a molecular weight of 40,000, 20 mg of sodium chloride, 2 mg of magnesium stearate and butylated hydroxide. Pharmaceutical composition comprising 400 mg by weight consisting of 0.16 mg of oxytoluene. The propellant composition of the 135 mg dosage form is a poly (alkylene oxide) having a molecular weight of 7,000,000, 99.23 mg of a poly (ethylene oxide), 27 mg of sodium chloride, 6.75 mg of hydroxypropylmethylcellulose having a molecular weight of 11,200, and black ferric oxide 1.24. Mg, magnesium stearate 0.675 mg, and butylated hydroxytoluene 1.108 mg. The internal epidermis of 93.1 mg consists of hydroalkyl cellulose and hydroxyethyl cellulose 88.45 mg of molecular weight of 90,000 and 46.55 mg of polyethylene glycol of 3,350 molecular weight. The outer shell of 51.1 mg consists of 30.66 mg of cellulose acetate having an acetyl content of 39.8%, 17.89 mg of hydroxypropyl cellulose having a molecular weight of 40,000, and 2.57 mg of polyethylene glycol having a molecular weight of 3,350. The average release rate (dm / dt) t of the formulation prepared by this example was 27 mg / hr in 4 to 9 hours.
    The delivery pattern of the formulation made by the present invention is illustrated in FIG. Non-uniform changes in the formulation are shown in FIG. 2. The showing of deviations is characterized by the substantial deviation of each system from the average release rate transition of the formulation at steady state. FIG. 2 shows that large polymer particles of 250 microns or more significantly change the hydration and drug delivery and flotation properties of the pharmaceutical composition. For this reason, there is a negative deviation with a large percentage difference in (dm / dt) i compared to (dm / dt) t .
    <Example 7>
    Formulations for oral delivery of a medicament to the gastrointestinal tract of a human body in need of drug treatment were prepared as follows: First, 6,000 g of Verapamil hydrochloride with a particle size of 150 microns or less, poly (ethylene) having a number average molecular weight of 300,000 and 250 microns or less Oxide) 3,047 g, powdered sodium chloride 500 g and 100 g poly (vinylpyrrolidone) having an average molecular weight of 40,000 were added to the coater and granulated in air for 5 minutes. Next, a solution prepared by dissolving 300 g of poly (vinylpyrrolidone) having a number average molecular weight of 40,000 in 4,500 g of distilled water is dispersed on the powder. The dispersion rate was 240 g / min, the inlet temperature was 45 ° C., and the air inflow was 1,000 cfm. The dispersion process is completed in two cycles: 30 seconds of solution dispersion, 2 seconds of drying, and 10 seconds of stirring to remove powder precipitates. At the end of solution dispersion the coated granulated particles are dried for an additional 25 minutes. The coated granules are made to a specific size using a flowing air mill. The granules were transferred to a mixer, mixed, smoothed with 50 g of magnesium stearate, and mixed with 4 g of butylated hydroxytoluene to prepare a pharmaceutical composition.
    Next, the propellant substitution composition is prepared as follows: First, 7,342 g of poly (ethylene oxide) having a number average molecular weight of 7,000,000, 2,000 g of sodium chloride, 2,000 g of hydroxypropylmethylcellulose having a number average molecular weight of 11,200 and black oxidation 100 g of ferric iron was added to the vessel of the fluid bed granulator. The granulation process was started and the powder was mixed for 6 minutes. Then, 300 g of hydroxypropylmethylcellulose having a number average molecular weight of 11,200 is dissolved in water to prepare a solution and to be dispersed on air-lifted particles. The coating step is as described above. The granules were sized using a flowing air mill and transferred to a mixer to prepare a pro- substituted composition by mixing 50 g of magnesium stearate and 8 g of butylated hydroxytoluene.
    The pharmaceutical composition and the propellant composition were then compressed into bilayer tablets as follows; First, 400 mg of the pharmaceutical composition containing 240 mg of verapamil hydrochloride was added to solidify, 135 mg of the propellant composition was applied thereon, and the two compositions were pressed at a pressure of 2,300 pounds to have a diameter of 7/16 inch (1.11 cm). The bilayer in contact was produced.
    Next, the compressed bilayer tablets were coated with epidermal laminates. The skin coat containing 95% of hydroxyethyl cellulose having a number average molecular weight of 90,000 and 5% of polyethylene glycol having a number average molecular weight of 3,350 was dissolved in distilled water to give a 5% solid solution. The composition forming the epidermis was dispersed around the bilayer tablet in a coater to form an enclosing outer layer. Dried skin was 93 mg.
    Next, the skin was coated with a semipermeable wall. The semipermeable composition included 60% cellulose acetate with an acetyl content of 39.8%, 35% hydroxypropylcellulose with a number average molecular weight of 40,000 and 5% polyethylene glycol with a number average molecular weight of 3,350. The film-forming composition was dissolved in a methylene chloride: methanol (90:10 weight: weight) cosolvent to prepare 4% solid solution. The semipermeable sheath was dispersed to surround the epidermis. The semipermeable wall was 51 mg.
    Then, two 27 mil (0.686 mm) outlet passages through the bilayer were drilled to connect the drug layer and the exterior of the formulation. Drying was carried out at 50 ° C. and 50% humidity for 96 hours to remove residual solvent. Finally, the osmotic, fluid absorbing formulation was dried at 50 ° C. for 2 hours to remove excess moisture.
    The formulation prepared by this example is the same as the composition in Example 6 except for the size of the controlled pharmaceutical particles and the size of the hydrophilic polymer particles in the pharmaceutical composition. This dual particle control provides a drug release pattern with substantially uniform dose release and virtually no significant change in width. 3 shows the drug delivery pattern of this example. 3 shows the release rate of (dm / dt) t equal to 27.9 mg / hr for 4 to 9 hours. Figure 3 shows that no variation was observed for the formulation provided by this example.
    <Example 8>
    Agents used in the formulation are israpine, nilvadipine, flulunarizine, nimodipine, diltiazem, nicardipine, nitridipine according to Example 7 except that it is a calcium channel blocker selected from the group consisting of nitridipine, nisoldipine, filodipine, amlodipine, amlodipine, cinnarizine and fendiline The formulation was prepared.
    Example 9
    The agent may be alacipril, benzazepril, cialzepril, captropril, delapril, enalapril, fosinopril, Angiotensin selected from the group consisting of lisinopril, moveltypril, perindopril, quinapril, ramipril, spirapril and zofenopril Except for the conversion enzyme inhibitor, the above-described procedure was repeated as it was previously used in the preparation conditions.
    <Example 10>
    D-alpha tocopherol, dl-alpha tocopherol, d-alpha tocopherol acetate, d-alpha tocopherol succinate, dl-alpha tocopherol succinate, dl-alpha tocopherol palmitate 0.05ng antioxidant selected from the group consisting of ascorbic acid, oleic acid ascorbyl, palmitic acid ascorbyl, butylated hydroxyanisole, butylated hydroxytoluene, sodium ascorbate, calcium ascorbate and gallic acid propyl stabilizer The procedure of the above example was used as is in this example except that an additional 7 mg was added.
    <Example 11>
    0.05ng to 7mg of antioxidants and 0.05ng to 7mg of lubricant selected from the group consisting of magnesium stearate, calcium stearate, magnesium oleate, magnesium palmitate, corn starch, tomato starch, bentonite, citrus pulp and stearic acid, The procedure of the above example was used in this example as it is except for adding 100% by weight of the pharmaceutical composition when expressing all components of the pharmaceutical composition in weight percent.
    <Example 12>
    Anionic, cationic, amphoteric and dialkyl sulfosuccinates, polyoxyethylene glycerol, polyoxyethylene stearyl ethers, propoxy-ethoxy copolymers, polyoxyethylene fatty alcohol esters, polyoxyethylene fatty acid esters, ethoxylated hydrogenated castor oils And 0.01 mg to 10 mg of a surfactant selected from nonionic surfactants including butoxylated hydrogenated castor oil to the pharmaceutical composition and from 0.01 mg to 10 mg of riboflavin to the pharmaceutical composition to stabilize the drug against sunlight. The procedure of this embodiment is followed in this embodiment as is, except for adding to the pharmaceutical composition as a means for protecting the medicament against sunlight and infrared light.
    Additional Initiation of the Invention
    Useful therapeutic agents for use in the specification and claims include medicaments. The term medicament includes warm-blooded mammals, humans and primates; Birds, pets, sporting and breeding animals; Laboratory animals; Pisces; reptile; And physiologically or pharmacologically active substances that have a local or total effect in animals, including zoo animals. The term "physiological" as used herein generally refers to the administration of a medicament that provides normal drug levels and functions. The term "pharmacological" as used herein generally means a change in response to the amount of drug administered to a subject to be administered. Pharmaceuticals are pharmacological such as molecules themselves, molecular complexes, hydrogen chloride, hydrogen bromide, sulfate, laurate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartarate, oleate, salicylate, etc. It may be in various forms such as salts. As acidic agents, salts, amines or organic cations of metals such as quaternary ammonium can be used. Derivatives of agents such as bases, esters and amides can be used. Insoluble agents are their water-soluble derivative forms or their bases which are converted by enzymes during their delivery by the osmotic system and hydrolyzed by the body's pH or other metabolism to form the original therapeutic activity. It can be used in the form of derivatives. The amount of medicament in the dosage form, ie the pharmaceutical composition, is 25 ng to 750 mg. Formulations containing a medicament may be administered once, twice or three times a day.
    Active agents that can be delivered include, but are not limited to, inorganic and organic compounds, peripheral nerves, adrenergic receptors, choline receptors, nervous system, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, neurological connections, endocrine system, hormone system, immune system, organ system And agents acting on the reproductive system, skeletal system, autocoid systems, nutrition and embryo design, autocoid suppression and histamine and physiological systems. Active agents that can be delivered to act on these animal systems include depressants, beta-blockers, hypnotics, sedatives, phychic energizers, tranquilizers, anticonvulsants, muscle relaxants, Steroids, anti-Parkinson's medications, anesthetics, anti-inflammatory agents, polypeptides, local anesthetics, muscle contractors, antibacterial agents, antimalarials, hormonal therapies, birth control pills, sympathetic stimulants, diuretics, antiparasitic agents, tumors, hypoglycemia, ophthalmitis, electrolytes Diagnostic agents, cardiovascular agents, calcium channel blockers, angiotensin converting enzyme inhibitors, and the like.
    Examples of medicaments that can be delivered from the formulations of the present invention include amifostine, prochlorperazine edisylate, iron sulfate, aminocapric acid, potassium chloride, mecamylamine hydro Chloride, procaineamine hydrochloride, amphetamine sulfate, benzpetamine hydrochloride, isoproternal sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, betanchol chloride, metabolite meta chloride Choline (methacholine chloride), pilocarpine hydrochloride (antropine sulfate), bromine metascopolamine bromide, iodine isopropamide iodide, tridihexyl chloride (tridihexethyl chloride), phenformin hydrochloride, methylphenidate hydrochloric acid Methylphenidate hydrochloride, oxprenolol hydrochloride, tartaric acid metroprolol, cimetidine hydrochloride, diphenidol, meclizine hydrochloride, Maleic acid prochlorperazine maleate, phenoxybenzamine, phenoxybenzamine, thiethylperzine, maleate, anicinone, diphenadione erythryl teranirate erythrityl teranitrate, dizozin, isofurophate, reserpine, acetazolamide, metazolamide, bendroflumenthiazide, chlorproprop Chlorpropamide, torazamide, chlormadinone acetate, phenaglycodol, allopurinol , Aluminum aspirin, methotrexate, acetyl sulfisoxazle, drythromycin, progestins, estrogen progrestational, corticosteroids , Hydrocortisone acetate, cortisone acetate, triamcinolone, methyltesterone, 17 beta-estradiol, ethynyl estradiol, ethynyl estradiol Estinyl estradiol 3-methyl ether, prednisolone, 17-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel norgestrel, norethindone, norethiderone, progesterone, norgestro ne), orethynodrei, aspirin, indomethacin, aprosen, aposenen, fenoprofen, sulidac, diclofenac, indolopro Pen (indoprofen), nitroglycerin (nitroglycerin), propanolol (proparnolol), metroprolol (metroprolol), valproate (vallproate), oxyprenolol (timoprenolol), timolol (atenool) , Alpreholol, cimetidine, clonidine, imipramine, levodopa, chloropropmazine, resperine, methylodopa, Dihydroxyphenyllalanine, pivaloyloxyethyl ester of ε-methylopa hydrochloride, theophylline, calcium gluconate ferrous lactate, ketopro Ketoprofen, ibupro (ibuprofen), ceparesin (cephalexin), erythromycin, haloperidol, hameperiodol, zomeprirac, vincamine, diazepam, phenoxybenzamine , Beta-blockers, nifedipine, diltiazem, isradipine, nilvadipine verapamil, flulunarizine, nimodipine, felodipine ), Calcium channel blockers such as amlodipine, cinnarizine and fendiline, angiotensin converting enzyme inhibitors that are substantially sulfur free, angiotensin converting enzyme inhibitors with sulfhydryl groups, angiotensin converting containing linear sulfides Enzyme inhibitors, angiotensin converting enzyme inhibitors containing cyclic sulfides, angiotensin converting enzyme inhibitors containing methylsulfonyl groups, ramipril, fosinopril, althio Altiopril, benazepril, libenzapril, alacepril, citazapril, cirazapril, cilazaprilate, perindopril, zopheno Zofenopril, enalapril, lisinopril, imidapril, imidapril, spirapril, lentrapril, captopril, delapril ), Alindapril, indolapril and quinapril; Angiotensin enzyme inhibitors represented by those selected from the group consisting of propranolol, naproxen, phenylpropanolamine, glipizide, venlafaxine and 1990 Pharmaceutical Sciences, 18th edition, edited by Remington and published by Mac Publishing Co., Eastern City, Pennsylvania, Physicians, Desk Reference 50th Edition, published in 1996 by Medical Economics Corporation, Montwald, NJ, and Drugs selected from the group consisting of useful agents already known in the drug release industry in the USP Dictionary, published in 1995 by the United States Phamacopeial Convention, Inc., Rockville, Maryland.
    The formulations of the present invention provide one or more outlet means. The outlet means co-operate with the drug core to release a uniform and substantially unchanging drug dose from the formulation. Outlet means may be provided while the formulation is made and may be provided during delivery of the medicament by the formulation in the fluid environment to be used. The term outlet means used in the present invention refers to a passageway, an aperture, an orifice, a bore, a pore, a micropore, a porous component capable of ejecting a drug. (porous element), diffuse, travel, migrate, hollow fiber, capillary tube, porous insert, porous overlay, fine It comprises one selected from the group consisting of a microporous member and a porous composition. The expression also includes compounds or polymers that can be eroded or dissolved or leached from the outer or wall or inner coating layer to create one or more outlets or multiple outlets. The compound or polymer is a group consisting of erosive polyglycolic acid or polylactic acid, gelatinous filaments, water-removable polyvinyl alcohol, inorganic, organic, acid, salt, oxide and carbohydrates in the outer or inner coating layer. Leaching compounds such as fluid removable pore formations selected from. One outlet or several outlets is selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talos, sodium chloride, potassium chloride, sodium citrate and mannitol to provide a pore outlet means for a uniform release rate. Can be made by leaching selected components. The outlet means may have a variety of shapes, such as round, triangular, square, elliptic, in order to release the drug from the formulation in a uniform release dosage. The formulation may be made to have one or more outlets on one or more surfaces. The outlet means can be made by a drill through either the outer coating layer or the inner coating layer using mechanical or laser or through both coating layers. Outlets and equipment for making outlets are described in U.S. Patents 3,845,770 and 3,916,899 by Theeuwes and Higuchi, U.S. Patents 4,063,064 by Sounder et al. And U.S. Patents by Theeuwes et al. US 4.088.864. Outlet means, including the application of a release pore made by aqueous leaching to provide a volume, size, shape and drug release pore, are described in US Pat. Nos. 4,200,098 and 4,285,987 by Ayer and Theeuwes. Is disclosed.
    Particles used for the purposes of the present invention are made by milling which can provide the size of the medicament according to a method suitable for the invention and the size of the hydrophilic polymer accompanying the medicament. Means for preparing the particles include spray drying, sieving, freeze drying, grinding, grinding, jet milling micronization and chopping to obtain finely divided particles of the intended size. The process includes a micropulverizer mill, a fluid energy grinding mill, a grinding mill, a roller mill, a hammer mill, an attrition mill, a chase mill, a ball mill, a vibrating ball mill , Size reduction equipment such as impact pulverizer mill, centrifugal mill, coarse mill, fine mill. The size of the particles is grizzly screen, flat screen, vibrating screen, revolving screen, shaking screen, oscillating screen and reciprocating screen ( This can be confirmed by screening including a reciprocating screen. The methods and equipment for preparing the particles are described in Pharmaceutical Sciences 17th Edition, pages 1585--1594 (1985) by Remington; Chemical Engineers Handbook 6th Edition, page 21, lines 13-19 (1984) by Perry; Journal of Pharmaceutical Sciences Volume 61, 6, pp. 813 to 829 (1974) by Parrot; And Chemical Engineers 94-103 (1990) by Higgsson.
    In accordance with the practice of the present invention, it has been found that dosages can be provided through semipermeable walls and are also suitable outer coating layers for the purposes of the present invention. The semipermeable wall is permeable to the flow of external fluids such as water and biological fluids, and substantially impermeable to the flow of active agents, osmotic agents, osmopolymers and the like. The optional semipermeable composition used to form the wall is not inherently erosive and insoluble in biological fluids for the shelf life of the formulation.
    Representative polymers that form the walls include semipermeable homopolymers, semipermeable copolymers, and the like. In one preferred embodiment, the composition comprises cellulose esters, cellulose ethers and cellulose ester-ethers. The cellulosic polymer has a degree of substitution (D.S.) of anhydroglucose units greater than zero and no greater than three. Degree of substitution means the average number of hydroxy groups present on the original anhydroglucose unit replaced by a substituent or replaced with another group. The anhydroglucose unit is partially or fully substituted with groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkylcarbonate, alkylsulfonate, alkylsulfamate, semipermeable polymer former Can be.
    The semipermeable composition typically comprises cellulose acylate, cellulose dicylate, cellulose triacelate, cellulose triacetate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alklate, mono- , Di- and tri-cellulose alkenylates and mono-, di- and tri-aroylates and the like. Typical polymers include cellulose acetate having a degree of substitution of 1.8 to 2.3 and an acetyl content of 32 to 39.9%; Cellulose diacetate having a degree of substitution of 1-2 and an acetyl content of 21-35%; Cellulose triacetate and the like having a degree of substitution of 2-3 and an acetyl content of 34-44.8%. More specific cellulosic polymers include cellulose propionate having a degree of substitution of 1.8 and a propionyl content of 38.5%; Cellulose acetate propionate having an acetyl content of 1.5 to 7% and a propionyl content of 39 to 42%; Cellulose acetate propionate having an acetyl content of 02.5 to 3%, an average propionyl content of 39.2 to 45%, and a hydroxyl content of 2.8 to 5.4%; Cellulose acetate butyrate having a degree of substitution of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; Cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; Cellulose triacylates having substitution degrees of 2.6 to 3, such as cellulose trivalerate, cellulose triamate, cellulose tripalmitate, cellulose trioctanate and cellulose tripropionate; Cellulose diesters having a degree of substitution of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanate, cellulose dicaprylate and the like; Mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptate, and the like. Semipermeable polymers can be synthesized by the method described in US Pat. No. 4,077,407 and published in Encyclopedia of Polymer Science and Technology, Vol. 3 (1964), pages 325-354, published by Interscience of New York.
    Another semipermeable polymer that forms the outer wall includes cellulose acetaldehyde dimethyl acetate; Cellulose acetate ethyl carbamate; Cellulose acetate methylcarbamate; Cellulose dimethylaminoacetate; Semipermeable polyamides; Semipermeable polyurethanes; Semipermeable sulfonated polystyrene; Crosslinked selective semipermeable polymers formed by coprecipitation of the following and various ions as disclosed in US Pat. Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,142; Semipermeable polymers disclosed in US Pat. No. 3,133,132 by Loeb et al .; Semipermeable polystyrene derivatives; Semipermeable poly (sodium styrenesulfonate); Semipermeable poly (vinylbenzylammonium chloride); Fluid permeability expressed as the difference in hydrostatic or osmotic pressure across the semipermeable wall per barometric pressure is 10 -5 to 10 -2 (cc.mil/cm ⋅ hr ⋅ atm) semipermeable polymers are included. Such polymers are known from US Pat. Nos. 3,845,770, 3,916,899 and 4,160,020 and the Handbook of Common Polymers of Scott, JR and Roff, WJ, published by CRC, Cleveland, Ohio.
    The epidermis of the present invention is located in contact with the inner surface of the semipermeable wall, and the outer semipermeable wall surrounds and surrounds the inner sheath. The inner skin has a thickness of 0.01 to 3 mm and includes one selected from the group consisting of hydroxyalkyl, hydroxyethyl cellulose, hydroxyisopropyl cellulose, hydroxybutyl cellulose and hydroxyphenyl cellulose. The hydroxyalkyl cellulose has a number average molecular weight of 9,500 to 1,250,000.
    The pharmaceutical composition comprises a hydrophilic polymer for providing the pharmaceutical composition with hydrophilic polymer particles that contribute to a uniform and unchanging drug delivery pattern. Representative examples of these polymers include poly (alkylene oxides) having a number average molecular weight of 100,000 to 750,000 such as poly (ethylene oxide), poly (methylene oxide), poly (butylene oxide), and poly (hexylene oxide); Poly (alkylene oxide) having a number average molecular weight of 40,000 to 400,000, such as poly (alkali carboxymethylcellulose), poly (carboxymethylcellulose sodium), poly (carboxymethylcellulose potassium) and poly (carboxymethylcellulose lithium) And selected from the group. The pharmaceutical composition is a hydroxypropyl having a number average molecular weight of 9,200 to 125,000 represented by hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose and hydroxypropylpentylcellulose to enhance the delivery properties of the formulation. Alkyl cellulose; And poly (vinylpyrrolidone) having a number average molecular weight of 7,000 to 75,000 to enhance the flow characteristics of the formulation.
    The contact layer arranged propellant-substituted composition comprises a polymer that absorbs the aqueous or biological fluid and swells to push the pharmaceutical composition out of the formulation through the outlet means. Representative examples of fluid-absorbing substituted polymers include poly (alkylene oxides) having a number average molecular weight of 1,000,000 to 15,000,000 represented by poly (ethylene oxide) and poly (alkali carboxymethylcellulose) having a number average molecular weight of 500,000 to 3,500,000 ( Alkali here includes sodium, potassium or lithium). Examples of additional polymers for formulation include probo-substituted compositions are Carbopol acidic carboxypolymers, also known as carboxypolymethylene and carboxyvinyl polymers having an molecular weight of 250,000 to 4,000,000, which are acrylic polymers and crosslinked with polyallyl sucrose; Cynamer table polyacrylamide; Crosslinked water swellable indenmaleic anhydride polymers; Good-rite polyacrylic acid having a molecular weight of 80,000 to 200,000; Osmotic polymers including polymers that form hydrogels such as Aqua-Keeps table acrylate polymer polysaccharides composed of condensed glucose units such as diester crosslinked polygluran. Representative polymers that form hydrogels are described in US Pat. No. 3,865,108 to Hartop; US Patent No. 4,002,173 to Manning; Known in US Pat. No. 4,207,893 by Michaels and in the Handbook of Common Polymers of Scott and Roff., Published by CRC of Cleveland, Ohio.
    Osmotic agents, also known as osmotic solutes and osmotic active agents, which show an osmotic pressure gradient through the outer wall and the epidermis, are sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, Potassium phosphate, mannitol, urea, inosital, magnesium succinate, tartarate raffinore, sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates.
    Representative solvents suitable for preparing the water activated layers and walls include inert inorganic solvents that do not adversely harm the material, capsule, and final laminated wall water activated layer. The solvents broadly include those selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n- Heptane, ethylene glycol monoethyl ether, ethylene glycol monotyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride nitroethane, nitropropane tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane , Aqueous solvents containing inorganic salts, such as benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, sodium chloride, calcium chloride, acetone and water, acetone and methanol, acetone With ethyl alcohol, methylene dichloride and methanol and ethylene dichloride Mixtures thereof such as the example of methanol.
    The semipermeable wall and the skin of the formulation can be made by one technique using an air suspension method. The method consists in lifting and inverting the bilayer core, the inner skin composition and the composition forming the outer semipermeable wall into the surrounding air until the skin and outer wall coatings can adhere to the bilayer core during either operation. The air flotation method is well suited for independently forming the walls of the formulation. The air flotation method is described in U.S. Patent Nos. 2,799,241; J. Am. Pharm. Assoc. Vol. 48 (1959), pp. 451-459; And Cos. 49 (1960), pp. 82-84. The formulation can also be coated using a Wurster Table air flotation coater, for example methylene dichloride methanol as cosolvent. Other coating techniques, such as pan coating, can be used to provide the formulation. In a pan coating system, a composition is formed that forms the skin on the wall by successive spraying of each compaction onto the bilayer core while inverting in a rotating pan. Fan coaters are used because they are readily available on a commercial level. Other techniques can be used to coat the pharmaceutical core. Finally, the wall or coated formulation is dried for one week in a 40 ° C. forced air oven or for 24 hours in an oven controlled at 40 ° C., 50% relative humidity, temperature and humidity free of solvent from the formulation.
    The formulations of the present invention are prepared by standard techniques. For example, one manufacture blends the active agent and other ingredients that make up the first layer facing the outlet means and compresses to form a solid layer. The layer has a volume corresponding to the internal volume of the region in which the layer will occupy the formulation and also has a volume corresponding to the second layer forming a contact arrangement. The pharmaceutical and other ingredients may be blended with a solvent and mixed in solid or semi-solid form by conventional methods such as ball milling, calendering, stirring or roll milling and then pressed into a preselected shape. Thereafter, the layer of the osmopolymer composition is contacted with the pharmaceutical layer in the same manner. The formulation layer and the osmopolymer layer can be prepared by conventional bilayer compression techniques. The two contacted layers are first coated with a skin and an outer semipermeable wall. The air flotation and air flip method supports the contacted first layer and the second layer compressed in the presence of air containing the composition that is later formed until the wall composition surrounds the first and second layers. Consists of flipping.
    In another method of preparation, the formulations are prepared by wet granulation techniques. In the wet granulation technique, the medicaments and components making up the first layer or pharmaceutical composition are mixed using an organic solvent such as denatured anhydrous ethanol as the granulation fluid. The components forming the first layer or pharmaceutical composition are each passed through a preselected screen and then thoroughly mixed in a mixer. Then, the other components constituting the first layer are dissolved in the granulation fluid, a part of the solvent. Thereafter, the wet mixture prepared later is slowly added to the drug mixture with continuous stirring in the mixer. The granulation fluid is added until a wet mixture is produced and the wet mixture mass is passed through a predetermined screen over an oven tray. The mixture is dried in a forced air oven at 24 ° C. to 35 ° C. for 18 to 24 hours. The size of the dried granules was measured. Next, magnesium stearate is added to the pharmaceutical granules and placed in a milling vessel and stirred for 10 minutes in a mill. The composition is pressed in one layer, for example in a Manesty table press. The compression speed is adjusted to 20 rpm and the maximum load is adjusted to 2 tons. The first layer is pressed against the composition forming the second layer and the bilayer tablets are injected into a Killan Mark Dry Coata press, surrounded by drug-free coating and outer wall solvent coating.
    Another method of preparation that can be used to provide the compartment forming composition comprises mixing the powdered components in a fluid bed granulator. After dry blending the powdered components to the granulator, a granulating fluid such as poly (vinylpyrrolidone) in water is sprayed onto the powder. The coated powders are dried in a granulator. This method granulates all the components present when adding the granulation fluid. After the granules are dried, lubricants such as stearic acid and magnesium stearate are mixed into the granules using a V-blender. The granules are pressed in the above manner.
    <Method of Carrying Out the Invention>
    The present invention provides a composition comprising a composition, a dosage of a drug in the composition and a hydrophilic polymer in the composition, (1) making a composition having a medicament having a particle size of 150 microns or less, and (2) having a hydrophilic polymer having a particle size of 250 microns or less The composition provides a method by which (1) and (2) coexist in the composition such that the agent is delivered from the formulation at a substantially uniform and unchanging release rate.
    The invention also encompasses a composition comprising a composition, a pharmaceutical dosage in the composition, a hydrophilic polymer in the composition and one composition for substituting the pharmaceutical composition from the formulation, and (1) a pharmaceutical composition having a particle size of 150 microns or less. And (2) a composition having a hydrophilic polymer having a particle size of 150 microns or less, so that the composition for substitution and (1) and (2) coexist so that the field composition absorbs the fluid, swells and removes the pharmaceutical composition from the formulation. Substitution is provided to allow the agent to be delivered from the formulation at a substantially uniform and unchanging release rate. The medicament is delivered for a long time at a substantially uniform and unchanging release rate.
    The present invention also provides a method for delivering a medicament to a patient. The method comprises (A) a semipermeable wall that surrounds a patient (1) to form a compartment; (2) pharmaceutical compositions within compartments; (3) a pharmaceutical dosage of less than 150 microns in particle size within the pharmaceutical composition; (4) a hydrophilic polymer having a particle size of 250 microns or less in the pharmaceutical composition; (5) enable oral administration of a formulation comprising an outlet outlet within the semipermeable wall; (B) absorbing fluid through the semipermeable wall into the pharmaceutical composition to form the disposable pharmaceutical composition into a dosage form through the co-operation of (2) and (3); (C) delivering the pharmaceutical composition to the patient through the outlet at a substantially uniform and unchanging dosage rate for a long time.
    The present invention also provides a drug delivery time of 1 to 15 hours by placing the epidermis in the formulation in contact with the inner surface of the semipermeable wall and surrounding the pharmaceutical composition or surrounding both the pharmaceutical composition and the propellant composition. A method of providing an intermediate without drug for from 5 hours. This method provides treatment for hypertension and laryngitis because it provides an intermediate period of no medication when the patient is less active, i.e. resting or dormant, and providing medication during times of waking up and waking up, mainly during the day of maximum activity. It is pointed out to use.
    The method also relates to the regulation of blood pressure control, systemic physiological control and time treatment (ie, time treatment by administering a medicament according to the manner and method of the present invention).
    The novel formulations of the present invention employ dual means to achieve accurate release rates of drugs that are difficult to deliver within the environment of use while maintaining the robustness and properties of this system. While the features and advantages of the present invention have been described and pointed out as indicated in this preferred embodiment, those skilled in the art of drug release technology will appreciate, various modifications and variations to this system described and described herein without departing from the spirit of the invention. , You will be able to make additions and deletions.
    权利要求:
    Claims (20)
    [1" claim-type="Currently amended] The formulation comprises a composition containing a pharmaceutical dose and a hydrophilic polymer, 1) formulating a composition containing a medicament having a particle size of less than 150 microns, and 2) formulating a composition containing a hydrophilic polymer having a particle size of less than 250 microns. And a step wherein 1) and 2) in the composition coexist to enable delivery of the medicament from the formulation at a substantially uniform release rate.
    [2" claim-type="Currently amended] The method of claim 1, wherein the composition provides a substantially uniform drug release rate from the formulation enclosed by a wall comprising means for releasing the medication from the formulation.
    [3" claim-type="Currently amended] The method of claim 1, wherein the composition provides a substantially uniform rate of drug release from the formulation enclosed by the inner sheath and the outer wall having means for releasing the medication from the formulation.
    [4" claim-type="Currently amended] The formulation comprises a pharmaceutical layer comprising a pharmaceutical dosage and a hydrophilic polymer and a dispersion layer comprising means for dispersing the pharmaceutical layer from the formulation, wherein the pharmaceutical layer comprises a pharmaceutical having a particle size of 150 microns or less and a hydrophilic polymer having a particle size of 250 microns or less Substantially uniform from the formulation, wherein the drug particles can be delivered at a substantially uniform release rate by the dispersing layer assisting the drug layer and the interaction of the drug particle particles with the hydrophilic polymer particles. A method for providing a drug release rate.
    [5" claim-type="Currently amended] The method of claim 4, wherein the hydrophilic polymer particles interact with the drug particles and the pharmaceutical carrier for delivering the drug from the formulation.
    [6" claim-type="Currently amended] The method of claim 4, wherein the dispersing layer aids in displacing the drug from the formulation.
    [7" claim-type="Currently amended] The method of claim 4, wherein the wall surrounds the drug layer and the dispersion layer and comprises means for releasing the drug from the formulation.
    [8" claim-type="Currently amended] 5. The method of claim 4, wherein the wall surrounds the skin layer between the drug layer and the dispersion layer and between the wall and the drug layer and the dispersion layer, and includes an outlet means for releasing the drug from the formulation. Way.
    [9" claim-type="Currently amended] a) a wall comprising a composition, b) a pharmaceutical dosage less than 150 microns in the composition, c) a hydrophilic polymer less than 250 microns in the composition, d) a pharmaceutical dosage and a composition surrounding the hydrophilic polymer and fluidly permeable, and e) a formulation from the formulation. A formulation for delivering a medicament comprising means present in the wall for delivering at a substantially uniform release rate.
    [10" claim-type="Currently amended] a coating layer surrounding a pharmaceutical composition comprising a) a pharmaceutical composition, b) a dosage of a pharmaceutical less than 150 microns in the pharmaceutical composition, c) a hydrophilic polymer less than 250 microns in the pharmaceutical composition, and d) means for delaying the release of the pharmaceutical from the pharmaceutical composition. e) a wall comprising a composition surrounding the coating layer and f) a means for delivering the medicament from the formulation for a long time.
    [11" claim-type="Currently amended] The pharmaceutical composition of claim 10, wherein the medicament is verapamil, nifedipine, nilvadipine, nilvadipine, flulunarizine, nimodipine, diltiazem, nicardipine ), Nitridipine, nisoldipine, felodipine, felodipine, amlodipine, isradine, israpine, cinnarizine and pendiline Formulations for Delivering Phosphorus Drugs.
    [12" claim-type="Currently amended] The pharmaceutical composition of claim 10, wherein the medicament is ramipril, fusinopril, altiopril, benazepril, libenzapril, alacepril, sialza. Cialzapril, cilazaprilat, perindopril, zofenopril, zoaprilop, inalapril, lisinopril, imidapril, spirapril The drug is selected from the group consisting of spirapril, rentiapril, captopril, delapril, delapril, orindaapril, indalapril, and quinapril. Formulations for Delivery.
    [13" claim-type="Currently amended] a) a pharmaceutical composition comprising a medicament having a particle size of less than 150 microns and a pharmaceutically acceptable hydrophilic polymer carrier of less than 250 microns for the medicament, b) means for introducing a fluid into the substitutional composition and substituting the influx of the fluid A substitution composition in contact with the pharmaceutical composition, wherein the volume of the composition expands to displace the pharmaceutical composition from the formulation, c) a wall surrounding the pharmaceutical composition and the substitution composition and comprising means for introducing a fluid into the formulation, and d) a pharmaceutical A formulation for delivery of a medicament comprising means present in the wall for delivering at a substantially uniform release rate during the release time.
    [14" claim-type="Currently amended] The formulation of claim 13, wherein the medicament is selected from the group consisting of calcium channel blockers and angiotensin enzyme inhibitors.
    [15" claim-type="Currently amended] The method of claim 13, wherein the agent is an alpha receptor blocker, a beta receptor blocker, an antianginal agent, an antiarrhythmic drug, an antiembolous drug, an antihypertensive agent, a cardiac agent, a hemoheologic drug, a muscle contractor, A dosage form for delivering a medicament selected from the group consisting of a prophylactic myocardial infarction, a cerebrovascular relaxant, a coronary relaxant, a peripheral vascular relaxant, and a vasoconstrictor.
    [16" claim-type="Currently amended] a) a pharmaceutical composition comprising a hydrophilic polymer carrier for a pharmaceutical having a particle size of 150 microns or less and a pharmaceutical having a particle size of 250 microns or less, b) a substitution composition that contrasts with the pharmaceutical composition and expands in the presence of a fluid to replace the pharmaceutical composition from the formulation c) a drug-free coating layer surrounding the agent and the replacement composition to slow the flow of fluid into the formulation, d) a wall surrounding the coating layer permeable to the passage of the fluid, and e) substantially uniform release of the drug for a long time. A formulation for oral delivery of a medicament to a patient in need thereof comprising a means present in the formulation for delivery at a rate.
    [17" claim-type="Currently amended] The formulation of claim 16, wherein the pharmaceutical composition comprises an antioxidant.
    [18" claim-type="Currently amended] The formulation of claim 16, wherein the pharmaceutical composition comprises a surfactant.
    [19" claim-type="Currently amended] 17. The pharmaceutical composition of claim 16, wherein the medicament in the pharmaceutical composition is verapamil, israpine, nifedipine, nilvadipine, flunarizine, nimodipine, diltia Diltiazem, nicardipine, nitridipine, nisoldipine, nisoldipine, felodipine, amlodipine, cinnarizine, fendiline, prazosin (prazosin), clonidine, (pinacidil) and afuzosin (afuzosin) formulation for delivery of a medicament selected from the group.
    [20" claim-type="Currently amended] 17. The pharmaceutical composition of claim 16, wherein the medicament is quinapril, indalapril, orindaapril, delapril, captopril, lentrapril, spirapril; spirapril, imidapril, lisinopril, enalapril, enalaprilat, zofenopril, perindopril, peridorpril (cilcizaprilat, cralzapril, alasepril, alacepril, libenzapril, benazepril, altropril, fosinopril and ramipril) Formulations for delivering a medicament selected from the group consisting of.
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    同族专利:
    公开号 | 公开日
    KR100468334B1|2005-03-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-04-05|Priority to US60/014,889
    1997-03-20|Application filed by 에드워드 엘.멘델, 앨자 코포레이션
    1997-03-20|Priority to KR10-1998-0707917A
    2000-01-25|Publication of KR20000005230A
    2005-03-16|Application granted
    2005-03-16|Publication of KR100468334B1
    优先权:
    申请号 | 申请日 | 专利标题
    US60/014,889|1996-04-05|
    KR10-1998-0707917A|KR100468334B1|1996-04-05|1997-03-20|Uniform Drug Deliver Therapy|
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