JP2002539165A - Controlled release of sildenafil delivered by sublingual or buccal administration - Google Patents

Abstract

  (57) [Summary] A controlled release composition containing sildenafil for delivery via the sublingual or buccal route. In addition to sildenafil, the composition comprises an osmotic agent, a swellable hydrophilic carrier, and a water-dispersible polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION [0001] The present invention relates to compositions for controlled release of water-soluble drugs for administration via either the sublingual or buccal routes. The present invention relates to a convenient treatment for sexual dysfunction in humans.

BACKGROUND OF THE INVENTION Sexual dysfunction in humans can result from a psychological cause (psychogenic erectile dysfunction) or an organic cause, or a combination thereof. Organic causes include physiological, neurological, cardiac and hormonal etiologies or combinations thereof.

[0003] The term "impossible" has been used to mean the inability of a male (male) to achieve and maintain a penile erection sufficient to permit satisfactory intercourse. The term "erectile dysfunction" has been suggested as the more specific term "means the inability of men to achieve erection penis as part of the overall multifaceted process of male sexual function." Droller, M .; J. Et al., "Impotence" Occurrence Conference Consensus Statement (Consensus Development Conference Statement), National Institutes of Health (1993).

[0004] The normal physiology of erection involves nerve impulses that generate signals that relax certain muscles. When contracted, these muscles restrict blood flow through arteries in the penis. When relaxed, the muscle allows a clear increase in blood flow. Increased blood flow causes three groups of erectile tissue in the penis to be reddened with blood, and the penis becomes less relaxed. The reddened erectile tissue and muscle structures of the penis suppress adjacent veins,
It restricts blood flow outside the penis. Restriction of blood flow outside the penis increases and maintains erection.

[0005] Deficiency of certain hormones, such as testosterone, or elevation of others, such as prolactin, can cause erectile dysfunction. Many drugs such as diuretics, antihypertensives, antispasmodics, anesthetics, alcohol, and psychotropics can cause erectile dysfunction as a side effect. Murray, F .; T. Amer
. J. Medical Sci. 309: 99-109 (1995).

[0006] Damage to nerves and blood vessels can also provide an organic cause for erectile dysfunction. The disease process can be involved in several aspects. For example, diabetes that causes damage to both nerves and blood vessels can cause erectile dysfunction. A clear proportion of all diabetic men suffer from erectile dysfunction.

[0007] In women, sexual dysfunction can increase with age and is associated with the presence of vascular risk factors that are the onset of menopause or is caused by hysterectomy.

[0008] Methods proposed for the treatment of erectile dysfunction include external devices, sexual intercourse, surgical implantation of endoprostheses, injection of drugs directly into the penis and topical dosing. Included. None of these approaches is entirely effective.

[0009] Oral pharmaceuticals are known to be particularly desirable and require an unobtrusive form of treatment for sexual dysfunction.

[0010] Recently, oral use of sildenafil citrate for the treatment of erectile dysfunction in men has been approved by the US Food and Drug Administration (FDA). Sildenafil is a dominant isozyme that metabolizes cyclic GMP formed in the corpus cavernosum, cyclic-
It is reported as a selective inhibitor of GMP-specific phosphodiesterase type 5 (PDE5). Because sildenafil is a potent inhibitor of PDE5 in the corpus cavernosum,
It is conceivable to enhance the effect of nitric oxide release. Nitric oxide can readily diffuse and stimulate the formation of increased cyclic guanosine monophosphate (GMP) in the corpus cavernosum by guanylate cyclase to relax smooth muscle cells,
The blood flow of the corpus cavernosum in the penis is increased, especially by sexual stimulation. 25-100mg
Sildenafil at the recently recommended dose of has little effect in the absence of sexual stimulation, so sildenafil restores the natural erectile response to sexual stimulation, but erections in the absence of such stimulation Is not considered to be caused. For example, G
Oldstein et al., "Oral Sildenafil" T in the Treatment of Erectile Dysfunction "
he New England Journal of Medicine ""
338, pp. 1397-1404 (1998). The local mechanism by which cyclic GMP stimulates smooth muscle relaxation is unclear.

In a dose response study, increasing doses of sildenafil (25 to 100
mg) is reported to increase the erectile efficacy of sildenafil. However, oral administration of sildenafil is also associated with undesired dose-dependent side effects. Ultimately, at doses higher than 50 milligrams, ranging from a blue or green hollow effect to cloudiness, indigestion, nasal congestion, flushing redness, diarrhea, dizziness, rash, and ureteral infection The occurrence of such side effects as an abnormal visual problem in
To increase.

Other more serious side effects have been reported such as syncope (loss of consciousness), priapism (erection lasting 4 hours or more), and increased risk of the heart (coronary artery of intercourse). Heart risk (coronary artery disease during sexual intercourse)
In certain cases, due to physiological predisposition, adverse drug interactions or synergism,
Or it can be caused by substance abuse. In particular, hypertensive attacks result from a combination of sildenafil citrate and an organic nitrate, which in certain instances may result in patients concurrently using an organic nitrate (such as nitroglycerin) in any form that causes death. In contrast, its administration is contraindicated.

Accordingly, there is a need and desire for an oral dosage form that promotes the biological utility of sildenafil at low doses with minimal side effects.

[0014] Sublingual tablets have been well described in the literature since the beginning of this century. The main reason for sublingual route drug administration is to provide a rapid onset of potent drug action. Another reason is to avoid first-pass metabolism by the liver. When used in sublingual tablets, the term "controlled release" is limited to a maximum of about 60 minutes. Traditional sublingual tablets are usually designed as water-soluble tablets made from water-soluble sugars such as sorbitol, lactose, mannitol and the like. In the literature, controlled release sublingual tablets are very rare.

In US Pat. No. 3,428,728 to Lowey (1969), gum arabic and sorbitol are cooked (by heating) until partially dried, followed by citric acid, a colorant and a flavoring agent. , Followed by chilled controlled release sublingual tablets are described. Thereafter, an active ingredient such as nitroglycerin, caffeine, guaiocholate, amylase or isoproterenol was added to the porous paste cast into tablets. However, Lowey's findings cannot be applied to making tablets by compression.

[0016] The time of release for a pharmaceutical product is important to the efficacy of the drug. The sublingual tablets of the present invention can be manufactured by the compression method, and can provide for controlled release of the drug.

SUMMARY OF THE INVENTION The present invention provides compositions that release drugs relatively slowly over an extended period of time. The composition is suitable for dosage form delivering the drug by the sublingual or buccal route. In the practice of the present invention with its use for the pharmacological agent sildenafil, a sublingual tablet formulation containing certain components will require a plasma concentration of its effective therapeutic agent below the plasma concentration at which unwelcome side effects occur. Let the drug achieve the concentration. In addition to this major improvement arising from the present invention, the additional benefit of controlled drug release from tablets is:
The bioavailability of the drug can be increased at concentrations lower than those required for conventional oral dosage forms.

[0018] In tablet form, the present invention provides a pharmacological, controlled rate that produces the desired physiological effect of a drug while preventing or reducing the side effects associated with sildenafil, such as headaches and stomach upsets. Delivers the drug sildenafil. Thus, such compositions provide the therapeutic benefit of sildenafil in the treatment of male erectile dysfunction with minimal side effects.

[0019] Delivering a drug and producing a suitable plasma concentration profile for an appropriate therapeutic effect is a major goal of therapeutic science. Many drug substances, when administered by conventional oral routes, tend to be poorly absorbed, too genetically unstable, or to produce apparently unwelcome effects. Substances such as sildenafil are rapidly metabolized through these pathways.

The previously available controlled release sublingual tablet formulations had a number of deficiencies. The present invention addresses these deficiencies, particularly in the following areas:

1. Time of release The time of release was limited to 15 to 60 minutes for sublingual controlled release tablets in previous studies. However, such time frames may not be practical for certain diseases and conditions. Similarly, this time frame may not be acceptable for many pharmacological agents.

2. Mechanisms for Controlling Drug Release For water-soluble drugs such as sildenafil, a hydrophilic diffusion-controlling matrix containing a water-dispersible polymer controls the dissolution and delivery of the drug in a time frame suitable for sublingual delivery There is work. The presence of an osmotic agent, such as mannitol, together with a hydrophilic swellable carrier also prevents a significant delay in drug release time.

[0023] 3. Drug Persistence Due to the instability associated with many drugs, such as sildenafil, embedding a drug in a polymeric matrix can reduce contact of the agent with ambient oxygen, humidity and light. Therefore, the choice of material must result in enhanced stability for the drug.

The composition of the present invention consists essentially of sildenafil, an osmotic agent, a swellable hydrophilic carrier and a water-dispersible polymer. Preferably, the osmotic agent is mannitol, the hydrophilic carrier is microcrystalline cellulose, and the water-dispersible polymer is a rubber or a cellulose derivative.

The present invention provides compositions suitable for sublingual or buccal tablets for relatively slow release of sildenafil. Further, the present invention provides a method of altering the composition that modulates drug release for optimal absorption, thereby increasing the bioavailability of the drug. Controlled drug release of a water-soluble drug can be used to enhance the therapeutic benefit of the drug, while at the same time reducing or eliminating its unwanted side effects.

The invention as described can be used especially for sildenafil. The practice of the present invention with sildenafil is preferred because increasing the bioavailability of this agent is useful in treating psychogenic disability. Furthermore, the present invention addresses the successful use of this drug at low concentrations without the major side effects that occur in highly undesirable and disabled men.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Sildenafil is chemically identified as 1-[[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4 , 3-d] pyrimidine-5
-Yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine and has the following structural formula:

[0028]

Embedded image Is shown.

As used herein, the term “sildenafil” refers to the free base form of this compound as well as its pharmacologically virus-acceptable acid addition salts formed with organic carboxylic acids, organic sulfonic acids or inorganic acids. Prepare. For the purposes of the present invention, 3.5 mg
Sildenafil citrate, an organic carboxylate that is soluble in / ml water, is particularly preferred. The literature for "sildenafil" comprises sildenafil citrate.

[0030] Sildenafil citrate is currently formulated for oral administration in tablets comparable to 25 mg, 50 mg and 100 mg sildenafil under the name Viagra ^™ (PfizerLabs).
, New York) is the active ingredient in commercial drug administration for disability. Depending on the manufacturer, in addition to the active ingredient sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, Contains lactose, triacetin, and FD & C Blue Number 2 aluminum lake.

[0031] The fact that sildenafil is approximately 4,000-fold more selective in inhibiting phosphodiesterase type 5 (PDE5) than other known phosphodiesterases, such as PDE3, which is involved in cardiac contractility control, has been demonstrated in vitro. Known from research. Sildenafil is reportedly only about 10-fold more potent for PDE5 than PDE6, an enzyme found in the retina, which is related to the color perception observed at higher doses or plasma concentrations It is this low selectivity that should be based on the anomalies made.

[0032] Sildenafil administered as a commercially available Viagra formulation is reported to be rapidly absorbed following oral administration with an absolute bioavailability of about 40%. Its pharmacology is proportional to dose over the recommended dose range. Based on the product literature of the Viagra® manufacturer, the highest observed plasma concentrations are achieved within 30 to 120 minutes (median 60 minutes) of oral administration in the fasting state. When the Viagra® formulation is taken with a high lipid diet, the rate of absorption is reduced with an average delay in T _max of 60 minutes and an average decrease in C _max of 29%. Mean steady state volume of the distribution for sildenafil (Vss)
Is reportedly 105 L, thereby indicating distribution into the tissue. Ninety minutes after dosing, based on reported measurements of sildenafil in semen of healthy volunteers, less than 0.001% of the administered dose was found in the semen of the patient.

The present invention provides formulations for controlled release tablets over a period of time suitable for sublingual or buccal drug delivery. For the compositions of the present invention, about 90 weight percent of the sildenafil present is released to the aqueous solution over a period ranging from about 25 minutes or more to about 300 minutes. In the confirming description and claims, the release time is quoted as the _T90 value. That is, the compositions of the present invention exhibit _T90 values ranging from about 25 minutes abnormal to about 300 minutes.

A tablet is made from a water-insoluble carrier, the porous structure of which is filled, coated, or covered with the active ingredient; an osmotic agent; and, if necessary, a stabilizing adjuvant. The above drug-loaded carrier system is then mixed with the water-dispersible polymer and directly compressed into tablets. With the tablet of the invention and a biological fluid such as saliva, and with the aid of osmotic agents, two opposing phenomena occur simultaneously.

1. Gelling of a water-dispersible polymer that delays diffusion of the drug from the tablet matrix. 2. Swelling of the water-insoluble carrier in the aqueous channel configuration also provides more surface area for fluid permeation, thereby leading to faster diffusion or release of the active ingredient.

For example, tablets containing microcrystalline cellulose as a water-insoluble carrier and mannitol (approximately 1: 1 w / w ratio) as a penetrant, and various water-soluble nonionic polymers can be used sublingually and And / or provide a controlled release rate of sildenafil suitable for buccal delivery.

Anionic macromolecules such as polyacrylates, sodium alginate or anionic gelatin further provide exceptional controlled rates of excipients for drug release. The exceptionally low rate of drug release from tablets containing anionic water-dispersible polymers is believed to be due to the presence of water-soluble organic acids present in these tablet matrices. These organic acids react with an anionic water-dispersible polymer in the presence of water or biological fluids such as saliva to form a further structured gel of the polymer (non-ionized In the form of anionic macromolecules).

The treatment of psychogenic impairment can be achieved by practicing the present invention. The practice of this technique requires administration of a sildenafil sublingual tablet, preferably about 15 to about 45 minutes before sexual activity.

[0039] Preferably, the sublingual dosage form dissolves in a period of at least about 2 minutes, but less than about 10 minutes. However, the lysis time can be long, if desired, as long as the required plasma concentration of sildenafil can be maintained. More preferably, the dissolution time in water for currently contemplated dosage forms is from about 3 minutes to about 5 minutes.

In general, preferred dosage forms contain sildenafil in the range of about 10 to about 75 milligrams, more preferably in the range of about 15 to about 50 milligrams, for treating psychogenic disability.

Suitable osmotic agents include mono- and disaccharides such as glucose, fructose, mannitol, sorbitol, lactose, and sucrose. Glycerin or urea can also be used. Organic and inorganic salts such as sodium chloride, potassium chloride and water-soluble polyelectrolytes are also suitable as permeants. A preferred penetrant is mannitol.

[0042] The swellable hydrophilic carrier may be selected from fillers suitable for use in compositions made by wet granulation. Suitable hydrophilic carriers are microcrystalline cellulose, ethyl cellulose, cross-linked polyvinyl pyrrolidone, fumed silica, silica, dicalcium phosphate, and calcium carbonate. Microcrystalline cellulose is a preferred hydrophilic carrier.

The swellable hydrophilic carrier preferably comprises about 2% of the composition, based on the weight of the composition.
Contains from 5 weight percent to about 40 weight percent.

The water-dispersible polymer can be a gum, an alginate such as sodium alginate, a cellulose derivative, gelatin, a water-soluble starch or other polymer. Suitable gums include tragacanth, acacia, guar gum.
Tragacanth rubber is preferred. Suitable cellulose derivatives include methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and the like. Preferred cellulose derivatives are hydroxypropyl methylcellulose (Methocel E4M Premium, NF
). Suitable polymers include polymethacrylic acid, polyacrylic acid, polysilicic acid and its salts, polylactic acid, carbomer, polycarbophil, polyvinyl alcohol, polyethylene glycol, nonionic alkoxy block copolymer, polysorbate, polymaleic acid and Equivalents are mentioned.

[0045] The water-dispersible polymer is preferably present in an amount of about 0,1 of the composition, based on the weight of the composition.
5 to about 20 weight percent. Preferably, the water-dispersible polymer comprises from about 6 weight percent to about 10 weight percent of the composition, based on the weight of the composition.

The weight ratio of permeant to swellable hydrophilic carrier is preferably from about 0.3 to about 4
Within the range. Preferably, for dosage forms containing the active ingredient in relatively high amounts, i.e., in the range of about 25 to about 75 milligrams, the weight ratio of penetrant to swellable hydrophilic carrier will be about 0.1. In the range of 35 to about 2. Relatively low volume,
That is, for dosage forms containing the active ingredient in the range of about 10 to about 25 milligrams, the weight ratio of penetrant to swellable hydrophilic carrier is in the range of about 0.7 to about 4. is there.

The compositions described in Examples 1-4 address the release and control of the mucosal absorption of sildenafil that allows for the desired plasma levels at the maximum concentration to be achieved.
The composition results in other apparent properties as well. Hydroxymethylcellulose in combination with microcrystals and mannitol, in the presence of saliva, increases and addresses the well-controlled release of sildenafil and thus acts as a matrix that controls the plasma concentration of the drug. In addition, these formulations can be flavored in addition to various sweeteners. The purpose of the flavor is double. Initially, a formulation flavored with a mild mint flavor provides the desirability of a sublingual tablet (which can remain under the tongue for up to 10 minutes). Second: The use of mint-type flavors can somewhat attenuate local emetic receptors located in the patient's oral / laryngeal area. This is desirable because it minimizes possible localization of the receptor by sildenafil, which can exacerbate the nausea associated with this drug.

The following examples are intended to illustrate, but not limit, the invention.

Example 1 Direct Compression Composition This example demonstrates the SL tablets A, B shown in Table 1 made by the direct compression method.
And C composition.

[0050]

[Table 1] Composition A is made by weighing the amounts of the components listed in Table 1.
Each component is passed through an appropriately sized (30 mesh) US sieve series screen. Sildenafil citrate, ascorbic acid, aspartam,
Dee & Sea Yellow 10 Lake, and citric acid are placed in a bun render and kneaded for an additional 5 minutes. Hydroxypropyl methylcellulose (
(Mesocel E4M, Premium) is added to the blender and mixing is continued for another 5 minutes. Thereafter, the microcrystalline cellulose (Avicel PH102) is placed in a blender and kneaded for another 5 minutes. Next, mannitol is added to the blender and kneaded for another 5 minutes. Finally, magnesium stearate,
Add to the blender and knead for another 2 minutes to obtain the final powder mixture. The final powder mixture is transferred to a suitable tablet press equipped with tools of the appropriate size and compressed into tablets. Compositions B and C are prepared according to the procedure of Composition A, except for the amounts of the components as indicated.

Example 2 Wet Granulation Composition This example illustrates a sublingual tablet composition DJ shown in Table 2 manufactured by a wet granulation method.

[0052]

[Table 2] Composition D is made from the components listed in Table 2 using a water-dispersible polymer, carbomer (Carbopol 974P). Weigh each component as indicated. Solutions containing sildenafil citrate, citric acid and ascorbic acid are prepared by dissolving the components in 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 and then adsorbed on the microcrystalline cellulose to form a mass. The mass is mixed in a stainless steel pan until homogeneous. The mass is granulated by screening through a No. 8 mesh screen and dried at about 60 to about 70 degrees Celsius for about 4 hours. The mass is mixed over time during this drying step.

The resulting dry granules are passed through a 32 mesh screen. The appropriate polymer and aspartam are kneaded with the dried granules for about 5 minutes using a twin-shell V-blender. At the end of the kneading cycle, magnesium stearate is added to the blender and kneading is continued for another 2 minutes to produce the final mixture.

The final mixture was removed from the blender and biconvex 7/3 for the tablet preparation
It is fed to a tablet press such as a stock single punch tablet press equipped with 2 "diameter tools. Tablets can be manufactured with various compression forces, thereby obtaining tablets of various hardness. .

With the exception of using the water-dispersible polymers listed in Table 2, the compositions EJ were:
It can be prepared by following the procedure for composition D.

Dissolution is performed at 37 ° C. using a dissolution medium of 700 ml of distilled water at 30 rpm.
The measurement can be performed using a United States Pharmacopeia (USP) Type II apparatus (USP XXIII) stirred at m. Sildenafil released into the medium can be analyzed by high pressure liquid chromatography (HPLC). The dissolution kinetics ( _Kdiss ) constant is calculated assuming first-order release kinetics.

Example 3 Wet Granulation Composition This example further illustrates the use of various water-dispersible polymers and compounds made by the wet granulation method in SL tablets KQ shown in Table 3 below. Is exemplified.

[0058]

[Table 3] The composition is prepared by weighing the individual amounts of the ingredients listed in Table 3, mixing the ingredients, and forming tablets by the wet granulation method described in Example 2.

Example 4 Direct Compression Composition This example further illustrates the use of a direct compression method to produce S as shown in Table 4 below.
L tablet compositions R and S are illustrated.

[0060]

[Table 4] Compositions R and S are made by weighing the individual amounts of the ingredients listed in Table 4, mixing the ingredients, and forming tablets by the direct compression method described in Example 1.

The foregoing is intended to be, but not limited to, examples of the present invention. Numerous variations and modifications may be made without departing from the true concept and scope of the invention.

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Claims (23)

[Claims] 1. A composition for providing controlled release of sildenafil by the sublingual route, comprising: a therapeutically effective amount of sildenafil; an osmotic agent; a swellable hydrophilic carrier; and a water-dispersible polymer. is configured, the ratio by weight of the swellable hydrophilic carrier by weight of the osmotic agent is in the range of from about 0.3 to about 4, the composition having a T ₉₀ in the range of about 300 greater than about 25 object. 2. The composition of claim 1, comprising from about 10 milligrams to about 75 milligrams of sildenafil. 3. The composition of claim 1, comprising from about 15 milligrams to about 50 milligrams of sildenafil. 4. The composition according to claim 1, wherein the osmotic agent is selected from the group consisting of sugars, glycerin, polyelectrolytes, organic salts and inorganic salts. 5. The composition according to claim 1, wherein the osmotic agent is mannitol. 6. The composition of claim 1, wherein the swellable hydrophilic carrier is selected from the group consisting of ethyl cellulose, microcrystalline cellulose, cross-linked polyvinyl pyrrolidone, dicalcium phosphate, calcium carbonate, and silica. 7. The composition according to claim 1, wherein the swellable hydrophilic carrier is microcrystalline cellulose. 8. The water-dispersible polymer is methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, alginate, gelatin, guar gum, tragacanth gum, gum arabic,
Consists of polyacrylic acid, polymethacrylic acid, polysilicic acid and salts thereof, polylactic acid, polymaleic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, nonionic block copolymer, carbomer, polycarbophil, polysorbate and soluble starch The composition of claim 1, wherein the composition is selected from the group consisting of: 9. The composition according to claim 1, wherein the water-dispersible polymer is methylcellulose. 10. The composition according to claim 1, wherein the water-dispersible polymer is carboxycellulose. 11. The composition according to claim 1, wherein the water-dispersible polymer is hydroxypropyl methylcellulose. 12. The composition according to claim 1, wherein the water-dispersible polymer is sodium alginate. 13. The method according to claim 1, wherein the water-dispersible polymer is tragacanth rubber.
A composition according to claim 1. 14. The composition according to claim 1, wherein the water-dispersible polymer is polyvinylpyrrolidone. 15. The composition according to claim 1, wherein the water-dispersible polymer is a carbomer. 16. The composition according to claim 1, wherein the water-dispersible polymer is polyethylene glycol. 17. The composition according to claim 1, wherein the water-dispersible polymer is gelatin. 18. The composition according to claim 1, comprising ascorbic acid palmitate, which is a water-dispersible compound. 19. The water-dispersible polymer comprises about 0.5 to about 0.5% by weight of the composition.
The composition of claim 1, comprising from about 20 weight percent to about 20 weight percent. 20. The swellable hydrophilic carrier comprises about 25, based on the weight of the composition.
2. The composition of claim 1, comprising from about 40 weight percent to about 40 weight percent. 21. The composition of claim 1, wherein the ratio of the weight of the osmotic agent to the weight of the swellable hydrophilic carrier is less than about 4. 22. The composition of claim 1, wherein the ratio of the weight of the osmotic agent to the weight of the swellable hydrophilic carrier is less than about 2. 23. A composition suitable for the treatment of psychogenic impairment, which provides for controlled release of sildenafil by the sublingual route, essentially comprising from about 10 milligrams to about 75 milligrams of sildenafil citrate; A swellable hydrophilic carrier; and a water-dispersible polymer, wherein the ratio of the weight of the osmotic agent to the weight of the swellable hydrophilic carrier is in the range of about 0.7 to about 4, and composition having a _{T 90} in the range of about 300 greater than about 25.