HK1022847A - Intranasal formulations for treating sexual disorders - Google Patents

Description

Intranasal formulations for the treatment of sexual disorders

The present invention relates to intranasal formulations of cyclic guanosine 3 ', 5' -monophosphate phosphodiesterase V (cGMP PDE5) inhibitors, particularly including the compound sedenafil, for the treatment of sexual disorders such as impotence. The invention also includes sedenafil mesylate (mesylate) and its formulations for intranasal administration and its use for the treatment of sexual disorders.

According to the specification of our international patent application WO94/28902, we have found that: the cGMPD 5 enzyme inhibitor compounds are very effective for the treatment of male erectile dysfunction (MED, impotence) and female sexual disorders. This finding led to the development of the compound sedenafil (5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl)]-1, 6-dihydroxy-1-methyl-3-propylpyrazolo [4, 3-d]Pyrimidin-7-ones) (VIAGRA)^TM) This compound has proven to be very successful for the first oral effective treatment of MED. WO98/53819, published 12/3 (after the priority date of the invention) in 1998, claims compositions for the intranasal administration of cGMP phosphodiesterase inhibitors, including sedenafil, for the treatment of erectile dysfunction.

For certain pharmaceutical products, the intranasal route of administration has been used as a mode of administration. The rate of absorption of an agent by the nasal cavity depends on a number of variable parameters; however, there are two key factors: surface area for absorption and local blood flow in the nasal cavity. The surface area for absorption is controlled by the nasal airflow resistance, which is controlled by the dense capillary bed in the erectable Carvernous tissue in the nasal cavity. Vasodilation of these tissues leads to nasal congestion or rhinitis, for example, which increases airflow resistance and reduces the available drug absorption surface area. However, vasodilation also increases blood flow and enhances absorption by increasing drug mobility at the site of absorption.

Vasodilation has been shown to have a wide range of effects on nasal drug absorption. Increasing nasal blood flow, nasal infections and rhinitis showed no effect on intranasal absorption of some agents, however these effects also showed that both increasing and decreasing absorption of other agents. Thus, it is unclear whether vasodilation enhances or reduces absorption by intranasal administration.

PDE5 enzyme inhibitors are potent vasodilators. PDE5 is shown to be located in the capillary bed of the nasal cavity. Thus, the enzyme inhibitor has promise in causing local vasodilation and nasal congestion. Intranasal administration of PDE5 inhibitors has the potential to increase local vasodilation and cause nasal congestion. Local increase in blood flow can enhance drug absorption, but vasodilation can cause nasal congestion and thus reduce the available absorption surface area. Also, the drug can cause local irritation. Thus, it is difficult to predict the effectiveness and acceptability of such agents for such routes of administration.

We have surprisingly found that: silenafil can be successfully administered by the intranasal route and following intranasal administration the drug is surprisingly more rapidly absorbed than the corresponding oral dose, resulting in a more rapid onset of action and therefore being effective at lower doses. Although, as mentioned above, PDE5 inhibitors have the effect of causing nasal congestion, this effect is not sufficient to inhibit rapid drug absorption.

Another factor that affects the absorption capacity of the following intranasal routes of administration of the product is water solubility. This allows the compound to be dissolved in the nasal mucosa tissue when administered as a powder. Also, when administered as a solution, only small amounts of nasal formulations (e.g. water sprays) can be used, and it is therefore important that a sufficiently high concentration of active ingredient is achieved to ensure that sufficient drug is delivered to each nasal cavity.

According to the present invention, we have found that: a particular salt of sedenafil, namely sedenafil mesylate, has surprisingly high water solubility, which makes it particularly suitable for use in aqueous intranasal formulations. sildenafil mesylate is a new class of salts of sildenafil which is a major aspect of the present invention. We have also found that: sildenafil mesylate forms crystalline monohydrate and dihydrate which have the advantage of being stable on long term storage, which is another feature of the described aspect of the invention.

In addition to being particularly suitable for intranasal administration, the sedenafil mesylate salt may be administered by a number of other routes where strong water solubility is an advantage.

Formulations for intranasal administration are well known in the art and may be presented as a powder or more generally as a nasal spray. These sprays typically include: solutions of the active agent in physiological saline or other pharmaceutically suitable liquid carriers. Various nasal spray compression pumps are also well known in the art and can be adjusted to deliver a predetermined dose of active drug.

The dosage of cGMP-PDE5 inhibitor released by the intranasal preparation is 1-100 mg/spray per nasal cavity, more preferably 5-20 mg/spray; the administration may be one or more times.

For solution formulations, a typical volume for each dose in each nasal cavity is 25-200. mu.l, more preferably 75-150. mu.l. The intranasal solution formulation may be administered as nasal drops from nasal drops or as an aerosol spray from a compressed bottle, single unit dose or metered pump spray. To avoid nasal irritation the pH can be controlled using standard buffer systems such as citrate, lactate or phosphate buffer systems, so that the formulation is preferably buffered to a pH of 3-8, more preferably to a pH of 4-7. In addition, the permeability must be adjusted with standard zymogens (e.g., sodium chloride, mannitol, or glucose) so that the formulation is isotonic.

In order to improve the chemical stability of the preparation, an additional stabilizing agent is added; i.e. antioxidants such as sodium metabisulphite, sodium bisulphite or vitamin E, or metal complexing agents such as ethylenediaminetetraacetic acid.

Single unit dose sprays can be prepared under sterile conditions or terminally sterilized to produce a sterile final product. Alternatively, a chemical preservative (such as benzalkonium chloride or benzyl alcohol) is used to maintain the multi-dose metered valve pump system free from microbial contamination.

Flavoring, perfuming and wetting agents may also be added to improve patient acceptability of the formulation.

One specific and preferred formulation comprises: a solution of active cGMP PDE5 inhibitor in 5% w/v glycerol in water.

In another particularly preferred aspect of the invention we find that: the use of a solubiliser (solubility enhancer) makes it possible to further increase the water solubility of sildenafil mesylate. Examples of suitable solubilizing agents include: xanthine (such as caffeine), vitamins (such as nicotinamide), and pharmaceutical adjuvants (such as vanillin and benzyl alcohol). Combinations of any of these agents are also possible.

Preferred solubilizers are caffeine (preferably at a concentration of 1.0 to 2.5% w/v); nicotinamide (preferably 3.0-20.0% weight/volume); vanillin (preferably 0.5-2.5% weight/volume); and benzyl alcohol (preferably 0.5-2.5% w/v). Also preferred are combinations of nicotinamide and vanillin. The use of these solubilizers makes it possible to increase the solubility of sildenafil mesylate in water from about 60mg/ml to over 100 mg/ml. This allows for more concentrated solutions to be administered to initiate the effect more rapidly and with reduced irritation. One particular and preferred formulation comprises: 100mg/ml sildenafil mesylate and 15mg/ml caffeine in a buffered aqueous solution. The pH of the solution is preferably adjusted to pH3-5, preferably to pH4.2 by the addition of a base such as sodium hydroxide.

The above formulation can be conveniently prepared by the following method: sildenafil mesylate, solubilizer and buffer are dissolved in water, adjusted for pH if necessary, sterilized by filtration or autoclave and then aseptically filled into spray bottles or other dispensers. Alternatively, sildenafil free base is added to a solution of methanesulfonic acid and a solubilizing agent (e.g., caffeine), stirred until dissolved, and buffer is added to adjust the pH prior to sterilization, as described above, and then bottled.

Powders overcome the stability problems associated with liquid formulations and are not limited by solubility and therefore can be delivered to the nasal cavity in high doses. Sildenafil mesylate may be formulated as a powder for nasal insufflation using a specialized delivery device (available from manufacturers such as Mait Spa, Italy; ValoisSA, France; Pfeiffer, Germany or Orion, Finland). The powder may be placed in a hard gelatin capsule, a folilbrister, or as an integral part of a single unit dose administration. Alternatively, a multi-dose dry powder system may also be employed.

Powder particle size is an important factor for successful administration to the nasal cavity. When the powder particles are smaller than 1 μm, the powder is easily inhaled through the nose and into the lungs; whereas larger powder particles do not have sufficient dissolution rate to be absorbed in the shorter residence time in the nasal cavity. According to the invention, the preferred particle size distribution in the powder is 1-l00 μm, more preferably 5-40 μm.

In addition, carrier powders such as lactose and glucose are often mixed with drug powders to aid in manufacturing and dose reproducibility (dose reproducibility) during intranasal administration.

Accordingly, the invention also includes a pharmaceutical formulation for intranasal administration for the treatment of male erectile dysfunction or female sexual dysfunction, which formulation comprises sildenafil mesylate and a pharmaceutically acceptable diluent or carrier in a form suitable for intranasal administration.

Dogs were used to evaluate the effectiveness of the intranasal formulation of the present invention. Four fasted dogs were lightly anesthetized and each received 5mg of the cGMP-PDE5 inhibitor in both nostrils. Both as a powder and as a solution. The plasma concentration of the active ingredient was measured and compared to the plasma concentration of the active ingredient obtained in dogs previously when the agent was orally administered.

The research result shows that: intranasal administration of sildenafil results in rapid and very high plasma concentrations compared to oral administration. sildenafil mesylate is very effective.

Thus, when the solution dose of 0.7mg/kg sildenafil mesylate was administered intranasally to four dogs, the mean peak plasma concentration was 407ng/ml over a period of 5 minutes. In contrast thereto: at an oral dose of 1.4mg/kg sildenafil citrate, a mean peak plasma concentration of 204ng/ml was obtained over a period of 136 minutes.

The above findings were also confirmed by human trials, and studies on volunteers showed that: for the following intranasal route of sildenafil mesylate, plasma concentrations of sildenafil were obtained as compared to the oral dose, with peaks in plasma concentrations occurring 5-15 minutes after dosing.

The following examples illustrate the preparation of the formulations of the present invention, and the preparation of sildenafil mesylate and its crystalline hydrates.

Example 1

Intranasal solution formulations

An intranasal solution formulation of the following composition was prepared: 1. sildenafil mesylate 50mg water for injection to 1ml2, sildenafil mesylate 50mg glucose 50mg water for injection to 1ml3, sildenafil mesylate 50mg glucose 50mg benzyl alcohol 10mg water for injection to 1ml4, sildenafil mesylate 25mg 5% w/v glycerol in water to 1ml5, sildenafil mesylate 50mg 5% w/v glycerol in water to 1ml of the above solution were sterile filtered and filled into plastic nasal spray bottles. Example 2 intranasal formulation of solutions for administration a solution was prepared containing: sildenafil methanesulfonate 10g caffeine 1.5g sodium dihydrogen phosphate 0.69g distilled water to 100ml, stirred the above components until dissolved, and adjusted to pH4.2 by adding 1M sodium hydroxide solution. The solution was sterilized by ultrafiltration or by autoclaving at 120 ℃ for 20 minutes and the cooled solution was aseptically loaded into a single dose nasal spray device for giving a unit dose of 100 microliters.

The caffeine was replaced with nicotinamide (5.0g), vanillin (1.5g) or benzyl alcohol (1.5g), and the composition was prepared in a manner similar to that described above.

Example 3

Intranasal powder

An intranasal powder of the following composition was prepared:

sidenafil methanesulfonate 5mg (A)

Lactose 35mg the above composition was ground to an average particle size of 20 μm and filled into gelatin capsules for commercial use by means of a nasal insufflator.

EXAMPLE 45 preparation of- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl ] -1, 6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d ] pyrimidin-7-one methanesulfonate (sildenafil mesylate)

(5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl)]-1, 6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d]Pyrimidine-7-ones¹(100g, 0.2lmol) was dissolved in boiling acetone (3000ml) and methanesulfonic acid (14.9ml, 0.23mol) was added to the hot acetone solution. A precipitate formed within 10 seconds. The mixture was cooled and allowed to granulate for 48 hours. The title product was collected by filtration and dried in vacuo to yield a white solid (116.0g, 96.8%), m.p.272-274 ℃. Elemental analysis: c₂₃H₃₄N₆O₇S₂Measured value: c, 48.33; h, 5.99; n, 14.68; theoretical value: c, 48.41; h, 6.00; n, 14.73%. Delta (CD)₃SOCD₃)²0.92(3H, t), 1.33(3H, t), 1.73(2H, heptad), 2.29(3H, s), 2.77(2H, t), 2.79(3H, s), 3.16(2H, br), 3.33-3.57(4H, br), 3.8(2H, br), 4.16(3H, s), 4.20(2H, q), 7.4(1H, d), 7.88(1H, dd), 7.90(1H, s), 9.44(1H, br).

EXAMPLE 55 preparation of- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl ] -1, 6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d ] pyrimidin-7-one methylsulphonate dihydrate (siledenafil mesylate dihydrate)

(5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl) at 55 ℃]-1, 6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d]Pyrimidine-7-ones¹(100g, 0.21mol) was dissolved in 2-butanone (1500ml) and heated under reflux. A solution of methanesulfonic acid (14.9ml, 0.23mol) dissolved in water (75ml) was added to the hot 2-butanone solution described above. After 20 minutes a precipitate formed. The mixture was cooled and allowed to granulate at ambient temperature for 6 hours. The subject product was collected by filtration and dried under air to give a white crystalline solid (119.5g, 93.5%). The dihydrate was heated in a melting point apparatus to obtain an amorphous state and melted at 272 ℃ and 274 ℃. Small samples were carefully dried for nmr and Karl Fischer analysis. Delta (CD)₃SOCD₃)²0.93(3H, t), 1.33(3H, t), 1.73(2H, hexameric peak), 2.29(3H, s), 2.62(2H, br), 2.76(2H, t), 2.79(3H, s), 3.15(2H, br), 3.29(HDO peak), 3.45(2H, br), 3.78(2H, br), 4.15(3H, s), 4.21(2H, q), 7.4(1H, d), 7.9(1H, s), 7.8(H, dd), 9.43(1H, br), 12.21(1H, s).

Water content (by Karl Fischer)³6.7% (theoretical dihydrate value of 5.93%)

1. Such as described in US5,250,534 and european patent 0463756

2. The instrument for NMR data measurement is a Varian Unity 300Spectrometer operating at 300MHz

3. The instrument for Karl Fischer data measurement is Metrohm 701KF TitrinoInstrument

EXAMPLE 65 preparation of- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl ] -1, 6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d ] pyrimidin-7-one methanesulfonate monohydrate (siledenafil mesylate monohydrate)

Anhydrous 5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl ] -1, 6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d ] pyrimidin-7-one methanesulfonate (1.082g) was suspended in a solution of acetone (19.4ml) and water (0.6 ml). The suspension was stirred at room temperature for 1 week, then 55. mu.l of water were added, after several days 30. mu.l of water were added, then 15. mu.l of water were added. The monohydrate crystals were collected by filtration and dried under air (yield 0.848mg, 84%). Thermogravimetric analysis showed: weight loss 1.21% at 80 ℃ followed by a further weight loss 1.76% at 125 ℃. Consistent with the monohydrate product.

Claims (10)

1. An intranasal pharmaceutical formulation for the treatment of male erectile dysfunction or female sexual dysfunction comprising: sildenafil mesylate, and a pharmaceutically acceptable diluent or carrier in a form suitable for intranasal administration.

2. An intranasal formulation according to claim 1, which is in the form of an aqueous solution or a powder.

3. An intranasal formulation according to claim 1, comprising sildenafil mesylate in 5% w/v glycerol in water.

4. An intranasal formulation according to claim 1, comprising sildenafil mesylate and caffeine in buffered aqueous solution.

5. An intranasal formulation according to claim 4, comprising: in aqueous solution buffered to pH4.2, 100mg/ml sildenafil mesylate and 15mg/ml caffeine.

6. An intranasal powder as claimed in claim 1, comprising: sildenafil mesylate having a particle size of 5 to 40 microns, and optionally a pharmaceutically acceptable carrier.

7. A pharmaceutical form for intranasal administration comprising: in an intranasal delivery system or device, silednafil mesylate and a pharmaceutically acceptable diluent or carrier according to any one of claims 1 to 6.

8. A method of treating male erectile dysfunction or female sexual dysfunction comprising: an effective amount of sildenafil mesylate is administered intranasally.

9. Cedenafil mesylate.

10. Cedenafil mesylate, crystalline monohydrate or dihydrate.