WO2000054777A1 - Liberation controlee de sildenafil administre par voie sublinguale ou orale - Google Patents

Liberation controlee de sildenafil administre par voie sublinguale ou orale Download PDF

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Publication number
WO2000054777A1
WO2000054777A1 PCT/US2000/006662 US0006662W WO0054777A1 WO 2000054777 A1 WO2000054777 A1 WO 2000054777A1 US 0006662 W US0006662 W US 0006662W WO 0054777 A1 WO0054777 A1 WO 0054777A1
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Prior art keywords
composition
water dispersible
sildenafil
dispersible polymer
weight
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Application number
PCT/US2000/006662
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English (en)
Inventor
Ragab El-Rashidy
Original Assignee
Pentech Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pentech Pharmaceuticals, Inc. filed Critical Pentech Pharmaceuticals, Inc.
Priority to JP2000604853A priority Critical patent/JP2002539165A/ja
Priority to EP00916328A priority patent/EP1171134A4/fr
Priority to AU37448/00A priority patent/AU3744800A/en
Publication of WO2000054777A1 publication Critical patent/WO2000054777A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • This invention relates to a composition for the controlled release of water-soluble drugs for administration via either sublingual or buccal route.
  • This invention also relates to a convenient treatment for sexual dysfunction in humans .
  • Background of the Invention sexual dysfunction in humans may result from psychological causes (psychogenic erectile dysfunction) or organic causes or a combination thereof .
  • Organic causes include physiological, nervous, vascular and hormonal pathologies or a combination thereof .
  • the term "impotence" has been used to signify the inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse.
  • erectile dysfunction has been suggested as a more precise term "to signify an inability of the male to achieve an erect penis as part of the overall multifaceted process of male sexual function.”
  • the normal physiology of an erection involves nerve impulses which signal certain muscles to relax. These muscles, when contracted, restrict blood flow through arteries in the penis. When relaxed, the muscles permit a significant increase in blood flow.
  • the increased blood flow engorges three groups of erectile tissue within the penis with blood and the penis becomes less flaccid.
  • the engorged erectile tissue and the muscle structure of the penis depress adjacent veins, restricting the flow of blood out of the penis.
  • the restriction of blood flow out of the penis increases and sustains the erection.
  • Deficiencies of some hormones can cause erectile dysfunction.
  • Many drugs such diuretics, antihypertensives, anticonvulsants, narcotics, alcohol, and psychotropic drugs may cause erectile dysfunction as a side effect.
  • Damage to nerves and blood vessels may also provide an organic cause for erectile dysfunction.
  • Disease processes may involve several aspects. For example, diabetes, which causes damage to both nerves and blood vessels, can cause erectile dysfunction. A significant percent of all diabetic men will suffer from erectile dysfunction.
  • sexual dysfunction can increase with age, and be associated with the presence of vascular risk factors, the onset of menopause or caused by hysterectomy.
  • sildenafil is reported to be a selective inhibitor of cyclic-GMP-specific phosphodiesterase type 5 (PDE5) , the predominant isozyme metabolizing cyclic GMP formed in the corpus cavernosum. Since sildenafil is a potent inhibitor of PDE5 in the corpus cavernosum, it is believed to enhance the effect of nitric oxide release.
  • PDE5 cyclic-GMP-specific phosphodiesterase type 5
  • Nitric oxide is readily diffusible, stimulates the formation of increased cyclic guanosine monophosphate (GMP) in the corpus cavernosum by guanylate cyclase to relax the smooth muscle cells thereby increasing cavernosal blood flow in the penis, especially with sexual stimulation.
  • GMP cyclic guanosine monophosphate
  • sildenafil is believed to restore the natural erectile response to sexual stimulation but not cause erections in the absence of such stimulation. See, for example, Goldstein et al . , "Oral Sildenafil in the Treatment of Erectile Dysfunction, " The New England Journal of Medicine, 338. pp 1397-1404 (1998) .
  • the localized mechanism by which cyclic GMP stimulates relaxation of the smooth muscles has not been elucidated.
  • sildenafil In dose-response studies, increasing doses of sildenafil (25 to 100 mg) reportedly increased the erectogenic efficacy of sildenafil.
  • the oral administration of sildenafil is also accompanied by dose-responsive undesirable side effects. Consequently, at dosages higher than 50 milligrams, the incidence of such side effects as abnormal vision problems ranging from blue or green halo effects to blurring, dyspepsia, nasal congestion, blinding headaches, flushing redness, diarrhea, dizziness, rash, and urinary tract infection increases.
  • Sublingual tablets are well documented in the literature since the beginning of this century.
  • the main reason for sublingual route of drug administration is to provide a rapid onset of action of potent drugs .
  • Another reason is to avoid the first pass metabolism by the liver.
  • the term "controlled release" when applied to sublingual tablets is limited to a maximum of about 60 minutes.
  • Traditional sublingual tablets are usually designed as water soluble tablets made of water soluble sugars such as sorbitol, lactose, mannitol, etc. In the literature, controlled release sublingual tablets are very scarce.
  • 3,428,728 to Lowey (1969) describes a controlled release sublingual tablet made by cooking gum acacia and sorbitol (by heating) till partial dryness followed by addition of citric acid, color and flavor followed by cooling. Active ingredients such as nitroglycerin, caffeine, guaiocolate, amylase or isoproterenol were then added to the pourable paste that was cast into tablets.
  • Active ingredients such as nitroglycerin, caffeine, guaiocolate, amylase or isoproterenol were then added to the pourable paste that was cast into tablets.
  • Lowey 's discovery cannot be applied to make tablets by compression. The time of release for a pharmaceutical preparation is critical to the effectiveness of the drug.
  • the sublingual tablet of the present invention can be prepared by compression method and provides a controlled drug release. Summary of the Invention
  • the present invention provides compositions that release drugs relatively slowly over an extended time period.
  • the composition is suitable for dosage forms that deliver drugs by the sublingual or buccal routes.
  • a sublingual tablet formulation that includes particular constituents permits the drug to achieve its effective therapeutic plasma concentration which is below a plasma concentration where undesirable side effects occur.
  • the added benefit of controlled drug release from the tablet can increase the bioavailability of the drug at a concentration lower than that required for conventional oral administration forms .
  • the composition in the form of a tablet, delivers the pharmacological agent, sildenafil, at a controlled rate to produce the desired physiological effect of the drug while preventing or diminishing the side effects, such as headache and upset stomach, that have been associated with sildenafil.
  • a composition thus provides the therapeutic benefits of sildenafil in the treatment of male erectile dysfunction with minimal side effects.
  • the previously available controlled release sublingual tablet formulations had a number of deficiencies .
  • the present invention addresses these deficiencies, especially in the following areas.
  • Time of release The time of release was limited from 15 to 60 minutes for a sublingual controlled release tablets in previous studies.
  • time frame may not be practical in the case of certain diseases and illnesses. Similarly, this time window may be unacceptable for a number of pharmacological agents .
  • Mechanism of controlling the release of the pharmacological agent For water soluble drugs, such as sildenafil, a hydrophilic diffusion-controlling matrix containing a water dispersible polymer will serve to control dissolution and release of the pharmacological agent within a time frame suitable for sublingual delivery. The presence of an osmotic agent, e.g., mannitol, along with hydrophilic, swellable, carrier will also prevent severe retardation of drug release time. 3. Stabilization of the pharmacological agent .
  • the imbedding of the pharmacological agent into a polymer matrix can reduce the contact of the agent with ambient oxygen, moisture and light.
  • the selection of materials should yield an enhanced stability for the pharmacological agent .
  • the present composition consists essentially of sildenafil, an osmotic agent, a swellable hydrophilic carrier and a water dispersible polymer.
  • the osmotic agent is mannitol
  • the hydrophilic carrier is microcrystalline cellulose
  • the water dispersible polymer is a gum or a cellulose derivative.
  • the present invention provides a composition suitable for sublingual or buccal tablets for the relatively slow release of sildenafil. Further, this invention provides ways of varying the composition to adjust drug release for optimal absorption, thereby increasing the bioavailability of the drug. Controlled drug release of the water soluble drug can be used to enhance the therapeutic benefit of the drug while at the same time reducing or eliminating its undesirable side effects .
  • This invention as described is particularly applicable to sildenafil.
  • the practice of this invention using sildenafil is desired since increasing the bioavailability of this drug is useful in the treatment of psychogenic impotence. Further, this invention allows for the successful use of lower concentrations of this drug without major side effects occurring in the impotent male which are extremely undesirable .
  • Sildenafil is designated chemically as l-[[3- (6, 7-dihydro-l-methyl-7-oxo-3-propyl-lH-pyrazolo [4, 3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methyl piperazine and has the following structural formula:
  • sildenafil as used herein includes the free base form of this compound as well as pharmacologically acceptable acid addition salts thereof formed with organo-carboxylic acids, organo-sulphonic acids or inorganic acids.
  • the organo-carboxylic acid salt, sildenafil citrate having a solubility in water of 3.5mg/ml is particularly preferred.
  • Reference to “sildenafil” includes sildenafil citrate.
  • Sildenafil citrate is presently the active ingredient of a commercial medication for impotence sold under the designation ViagraTM (Pfizer Labs, NY) formulated in tablets equivalent to 25 mg, 50 mg and 100 mg sildenafil for oral administration.
  • each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, lactose, triacetin, and FD&C Blue #2 aluminum lake .
  • sildenafil is approximately 4,000 fold more selective for inhibiting phosphodiesterase type 5 (PDE5) than on other known phosphodiesterases, such as PDE3 , which is involved in control of cardiac contractility.
  • Sildenafil is reportedly only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina and it is this lower selectivity which is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels .
  • Sildenafil administered as the commercially available ViagraTM formulation, is reported to be rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Its pharmacokinetics are dose-proportional over the recommended dose range. Based on the ViagraTM manufacturer's product literature, maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When the ViagraTM formulation is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T ax of 60 minutes and mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is reportedly 105 L, indicating distribution into the tissues. Based upon reported measurements of sildenafil in the semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose appeared in the semen of the patients .
  • Vss steady state volume of distribution
  • the present invention provides formulations for controlled release tablets in a time course suitable for sublingual or buccal drug delivery.
  • about 90 percent by weight of the sildenafil present is released in a water solution over a time period in the range of more than about 25 minutes to about 300 minutes.
  • the release time is referred to as a T 90 value. That is, the present compositions have a T 90 value in the range of more than about 25 minutes to about 300 minutes .
  • Tablets are made of a water- insoluble carrier whose porous structure is filled, coated, or covered by the active ingredient; an osmotic agent; and if necessary, a stabilizing adjuvant.
  • the above drug- loaded carrier system is then mixed with. a water dispersible polymer and subjected to direct compression into a tablet.
  • biological fluids such as saliva
  • osmotic agent a stabilizing adjuvant
  • the treatment of psychogenic impotence can be achieved by the practice of this invention.
  • the practice of this art entails the administration of the sildenafil sublingual tablet preferably about 15 to about 45 minutes prior to sexual activity.
  • sublingual dosage forms dissolve within a time period of at least about 2. minutes but less than about 10 minutes.
  • the dissolution time can be longer, however, if desired as long as the necessary plasma concentration of sildenafil can be maintained. More preferably, the dissolution time in water for the presently contemplated dosage forms is about 3 minutes to about 5 minutes .
  • a preferred dosage form contains sildenafil in a range of about 10 to about 75 milligrams, more preferably in a range of about 15 to about 50 milligrams for treating psychogenic impotence.
  • Suitable osmotic agents include monosaccharide and disaccharide sugars, such as glucose, fructose, mannitol, sorbitol, lactose, and sucrose. Glycerin or urea may also be used. Organic and inorganic salts, such as sodium chloride, potassium chloride and water soluble polyelectrolytes, are also suitable as osmotic agents .
  • a preferred osmotic agent is mannitol .
  • the swellable hydrophilic carrier may be chosen from fillers suitable for use in compositions made by the wet granulation process .
  • Suitable hydrophilic carriers are microcrystalline cellulose, ethyl cellulose, cross-linked polyvinylpyrrolidone, fumed silica, silica, dicalcium phosphate, and calcium carbonate. Microcrystalline cellulose is a preferred hydrophilic carrier.
  • the swellable hydrophilic carrier preferably comprises about 25 weight percent to about 40 weight percent of the composition based on the weight of the composition.
  • the water dispersible polymer may be a gum, alginate, such as sodium alginate, cellulose derivatives, gelatin, water soluble starch or other polymer.
  • Suitable gums include gum tragacanth, gum acacia and guar gum; gum tragacanth is preferred.
  • Suitable cellulose derivatives include methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose and the like.
  • a preferred cellulose derivative is hydroxypropyl methylcellulose (Methocel E4M Premium, NF) .
  • Suitable polymers include polymethacrylic acid, polyacrylic acid, polysilicic acid and salts thereof, polylactic acid, carbomers, polycarbophils, polyvinyl alcohol, polyethylene glycol, nonionic alkyloxy block copolymers, polysorbates, polymaleic acid and the like.
  • the water dispersible polymer preferably comprises about 0.5 weight percent to about 20 weight percent of the composition based on the weight of the composition.
  • Preferably the water dispersible polymer comprises about 6 weight percent to about 10 weight percent of the composition based on the weight of the composition.
  • the ratio of the amount by weight of the osmotic agent to the amount by weight of the swellable hydrophilic carrier preferably is in the range of about 0.3 to about 4.
  • the ratio of the amount by weight of the osmotic agent to the amount by weight of the swellable hydrophilic carrier is in the range of about 0.35 to about 2.
  • the ratio of the amount by weight of the osmotic agent to the amount by weight of the swellable hydrophilic carrier is in the range of about 0.7 to about 4.
  • compositions described in Examples 1-4 allow for the release and control of mucosal absorption of the sildenafil permitting the desired plasma levels at the concentration maximum to be achieved.
  • the composition affords other significant attributes as well. Hydroxymethylcellulose in combination with microcrystalline and mannitol perform as a matrix where in the presence of saliva, swell and allow for the sufficiently controlled release of the sildenafil, thus controlling the plasma concentration of the drug.
  • these formulae can be flavored in addition to a variety of sweeteners. The purpose of the flavoring agents is two fold. First: the formulation flavored with a mild mint flavor affords to the desirability of the sublingual tablet (which can remain under the tongue for up to 10 minutes) .
  • mint type flavors can attenuate some of the local emesis type receptors located in the oral/pharyngeal region of the patient. This is desirable because it minimizes possible localized stimulation of the receptors by sildenafil which can exacerbate nausea associated with this drug.
  • Example 1 Direct Compression Compositions
  • Composition A is prepared by weighing the amounts of the ingredients listed in Table 1. Each ingredient is passed through an appropriate sized (30 mesh, U.S. Sieve Series screen. The sildenafil citrate, ascorbic acid, aspartame, D&C yellow 10 Lake, and the citric acid are placed into a blender and blended for 5 minutes. Hydroxypropyl methylcellulose (Methocel ⁇ E4M, Premium) is added to the blender and mixing is continued for an additional 5 minutes. Microcrystalline cellulose (Avicel ⁇ j ⁇ PHI02) is then added to the blender and mixing is continued for an additional 5 minutes. Next, the mannitol is added to the blender and mixed for an additional 5 minutes. Finally, the magnesium stearate is added to the blender and mixed for an additional 2 minutes to yield a final powder mix. The final powder mix is transferred to a suitable tableting machine equipped with the appropriate sized tooling and compressed into tablets.
  • Compositions B and C are prepared by following the procedure of Composition A, except for the amounts of ingredients as indicated.
  • This example illustrates sublingual tablet compositions D-J shown in Table 2 below prepared by wet granulation method.
  • Composition D is prepared from the ingredients listed in Table 2 employing the water dispersible polymer, carbomer (Carbopol ⁇ 974P) . Each ingredient is weighed as indicated.
  • a solution containing sildenafil citrate, citric acid, and ascorbic acid is prepared by dissolving the ingredients into a mixture of equal volumes of purified water and ethanol, USP. The solution is warmed slightly, and mannitol is added. The solution is mixed until clear, then absorbed onto the microcrystalline cellulose to form a mass. The mass is mixed in a stainless steel pan until uniform. The mass is granulated by screening through a #8 mesh screen and then dried at about 60 to about 70 degrees Celsius for about 4 hours . The mass is mixed periodically during this drying step.
  • the resultant dried granules are passed through a 32 mesh screen.
  • the appropriate polymers and aspartame are blended with the dried granules for a period of about 5 minutes using a twin shell V-shaped blender.
  • magnesium stearate is added to the blender and the blending is continued for an additional 2 minutes to produce a final mix .
  • Tablets may be prepared at various compression forces, yielding tablets of different hardnesses .
  • compositions E-J may be prepared by following the procedure for Composition D.
  • Dissolution may be measured using USP Type II apparatus (USP XXIII) stirred at 30 rpm employing a dissolution medium of 700 ml of distilled water at 37 degrees Celsius. Sildenafil released into the medium may be analyzed by high pressure liquid chromatography (HPLC) .
  • Dissolution kinetic (K diSS ) constants are calculated assuming first-order release kinetics.
  • Example 3 Wet Granulation Compositions This example further illustrates SL tablets K-
  • Carbomer (Carbopol 974P) - - - 10 - - - -
  • compositions are prepared by weighing the respective amounts of the ingredients listed in Table 3, mixing the ingredients and forming the tablets by the wet granulation method described in Example 2.
  • Example 4 Direct Compression Compositions
  • This example illustrates further SL tablet compositions R and S shown in Table 4 below prepared by direct compression method.
  • compositions R and S are prepared by weighing the respective amounts of the ingredients listed in Table 4, mixing the ingredients and forming tablets by the direct compression method as described in Example 1.

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Abstract

L'invention concerne une composition à libération contrôlée contenant du sildénafil, destinée à être administrée par voie sublinguale ou orale. Outre le sildénafil, la composition comprend un agent osmotique, un support hydrophile pouvant gonfler et un polymère dispersible dans l'eau.
PCT/US2000/006662 1999-03-16 2000-03-14 Liberation controlee de sildenafil administre par voie sublinguale ou orale WO2000054777A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000604853A JP2002539165A (ja) 1999-03-16 2000-03-14 舌下またはバッカル投与により送出されるシルデナフィルの制御放出
EP00916328A EP1171134A4 (fr) 1999-03-16 2000-03-14 Liberation controlee de sildenafil administre par voie sublinguale ou orale
AU37448/00A AU3744800A (en) 1999-03-16 2000-03-14 Controlled release of sildenafil delivered by sublingual or buccal administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US26895799A 1999-03-16 1999-03-16
US09/268,957 1999-03-16

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WO2000054777A1 true WO2000054777A1 (fr) 2000-09-21

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PCT/US2000/006662 WO2000054777A1 (fr) 1999-03-16 2000-03-14 Liberation controlee de sildenafil administre par voie sublinguale ou orale

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EP (1) EP1171134A4 (fr)
JP (1) JP2002539165A (fr)
AU (1) AU3744800A (fr)
WO (1) WO2000054777A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990088249A (ko) * 1998-05-15 1999-12-27 디. 제이. 우드, 스피겔 알렌 제이 약학제제
WO2004030648A1 (fr) * 2002-09-25 2004-04-15 Capsulution Nanoscience Ag Forme d'administration solide a liberation rapide et destinee a une application orale de principes actifs a solubilite reduite
WO2010115576A1 (fr) * 2009-04-06 2010-10-14 Ratiopharm Gmbh Comprimé orodispersible contenant un sel de sildénafil
WO2011019819A1 (fr) * 2009-08-12 2011-02-17 Forest Laboratories Holdings Limited Compositions à désintégration orale de linaclotide
EP2374479A2 (fr) * 2008-12-17 2011-10-12 Dong-A Pharm.Co., Ltd. Composition à libération contrôlée pour produire une préparation à libération prolongée contenant de l'udénafil
CN107827895A (zh) * 2015-07-23 2018-03-23 青岛华之草医药科技有限公司 一种制备治疗男性勃起功能障碍的枸橼酸西地那非化合物的方法
SE2050532A1 (en) * 2020-05-07 2021-11-08 Liw Innovation Ab New compositions for oral or nasal use
US11672761B2 (en) 2020-11-16 2023-06-13 Orcosa Inc. Rapidly infusing platform and compositions for therapeutic treatment in humans

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CA2612917A1 (fr) * 2005-06-23 2007-01-04 Schering Corporation Formulations orales a absorption rapide d'inhibiteurs de la pde5
WO2007018057A1 (fr) * 2005-08-05 2007-02-15 Freund Corporation Comprime se desintegrant rapidement dans la cavite buccale et son procede de fabrication

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US5624677A (en) * 1995-06-13 1997-04-29 Pentech Pharmaceuticals, Inc. Controlled release of drugs delivered by sublingual or buccal administration

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US5346901A (en) * 1990-06-20 1994-09-13 Pfizer Inc. Pyrazolopyrimidinone antianginal agents
US5719283A (en) * 1990-06-20 1998-02-17 Pfizer Inc. Intermediates useful in the synthesis of pyrazolopyrimidinone antianginal agents
US5624677A (en) * 1995-06-13 1997-04-29 Pentech Pharmaceuticals, Inc. Controlled release of drugs delivered by sublingual or buccal administration

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990088249A (ko) * 1998-05-15 1999-12-27 디. 제이. 우드, 스피겔 알렌 제이 약학제제
WO2004030648A1 (fr) * 2002-09-25 2004-04-15 Capsulution Nanoscience Ag Forme d'administration solide a liberation rapide et destinee a une application orale de principes actifs a solubilite reduite
JP2006503855A (ja) * 2002-09-25 2006-02-02 カプサルーション ナノサイエンス アクチェン ゲゼルシャフト 難溶性活性成分を含む速放性の投与形態
EP2374479A2 (fr) * 2008-12-17 2011-10-12 Dong-A Pharm.Co., Ltd. Composition à libération contrôlée pour produire une préparation à libération prolongée contenant de l'udénafil
EP2374479A4 (fr) * 2008-12-17 2012-09-12 Dong A Pharm Co Ltd Composition à libération contrôlée pour produire une préparation à libération prolongée contenant de l'udénafil
WO2010115576A1 (fr) * 2009-04-06 2010-10-14 Ratiopharm Gmbh Comprimé orodispersible contenant un sel de sildénafil
US8933081B2 (en) * 2009-04-06 2015-01-13 Ratiopharm Gmbh Melting tablet containing a sildenafil salt
WO2011019819A1 (fr) * 2009-08-12 2011-02-17 Forest Laboratories Holdings Limited Compositions à désintégration orale de linaclotide
CN107827895A (zh) * 2015-07-23 2018-03-23 青岛华之草医药科技有限公司 一种制备治疗男性勃起功能障碍的枸橼酸西地那非化合物的方法
SE2050532A1 (en) * 2020-05-07 2021-11-08 Liw Innovation Ab New compositions for oral or nasal use
SE544672C2 (en) * 2020-05-07 2022-10-11 Liw Innovation Ab New compositions for oral or nasal use
US11672761B2 (en) 2020-11-16 2023-06-13 Orcosa Inc. Rapidly infusing platform and compositions for therapeutic treatment in humans

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JP2002539165A (ja) 2002-11-19
AU3744800A (en) 2000-10-04
EP1171134A1 (fr) 2002-01-16

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