AU4591602A - Nasal melatonin composition - Google Patents

Description

AUSTRALIA

Patents Act 1990 FRANCISCUS W H M MERKUS COMPLETE SPECIFICATION STANDARD PATENT Invention Title.

Nasal melatonin composition The following statement is a full description of this invention including the best method of performing it known to us:- NASAL MELATONIN COMPOSITION

DESCRIPTION

This invention relates to a pharmaceutical composition for intranasal s administration of melatonin. The invention further relates to doses or dosage units for intranasal administration, and the use of the same for the preparation of an intranasal dosage form.

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone secreted to from the pineal gland. It has been disclosed in numerous references that melatonin induces sleep when administered to a patient. The sleep-inducing effects of melatonin have advantages over conventional hypnotics, since not being a hypnotic drug itself, it only induces a state of sleepiness without having the adverse side-effects of conventional hypnotics. Melatonin is is usually administered orally but, as with most oral preparations, it takes over an hour after administration for the blood plasma concentration of the active agent (melatonin) to reach its peak. Other routes of administration, in particular nasal administration have been considered. However, because of inherent problems, inter alia due to the low solubility of melatonin in water, melatonin compositions suitable for nasal administration have yet to be prepared.

In an early attempt to develop such a composition, Vollrath et al., Adv.

Bioscience, 29 (1981), pp. 327-329 described the nasal administration of 1.7 mg of melatonin in ethanol. Due to serious local irritation and painful administration, this composition was found to be unsuitable for use in man. In 1980, intranasal compositions containing reduced quantities of ethanol were disclosed in Japanese patent application J55C57563 (Hoechst AG). A compositiho of 100 mg of melatonin in 10 mi of a 5% solution of jo ethanol in water was proposed, but even this still causes an unacceptable degree of adverse side-effects. This patent application also disclosed a composition in which propyiene glycol was used in place of etharol.

Although this second composition would not cause the acute problems associated with ethanol, it is not suitable for nasal use because of the toxicity of propylene glycol, which adversely affects the nasal mucosa.

Therefore, up until the present time, a pharmaceutically acceptable melatonin composition, capable of providing a fast onset time, has yet to be developed.

This problem has now been solved in accordance with the present invention which provides, in a first aspect, a powdered pharmaceutical composition when used for intranasal administration, the composition comprising melatonin and a pharmaceutically acceptable excipient, characterised by being effective to cause the blood plasma concentration in a human adult, receiving an amount of melatonin in the range of 50-1000 ig and in a single dose or simultaneous intranasal administration of said composition, to reach at least Xpg/ml, within 30 minutes of said administration, wherein X is equal to 5 times the amount of melatonin, expressed in gg, in said single or simultaneous administration.

X is preferably equal to 10, 15, 20 or 25 times the quantity of melatonin, expressed in pg, in said single or simultaneous administration and the amount of melatonin in said administration can be in the range of 100-800 or 200-400 mg. Preferably, a composition in accordance with the invention is effective to cause the blood plasma melatonin concentration in a human adult, receiving 200 p.g of melatonin in a single or simultaneous intranasal administration of said composition, to reach at least 1000pg/ml and, preferably, at least 2000, 3000, 4000, or 5000pg/ml, within 30 minutes of administration.

In preferred embodiments, said melatonin concentrations are reached within 15, 10, 8, 7, 6 or 5 minutes of administration. Compositions in accordance with this aspect of the invention can also comprise a saccharide, a polysaccharide or a triol.

In further preferred embodiments, compositions in accordance with the present invention, when intranasally administered, are effective to cause a peak blood plasma melatonin concentration, or a t(max) within 30 minutes of administration and, preferably, within 15 or 10 minutes of administration.

Preferably, compositions in accordance with this aspect of the invention comprise less than 5-1% by volume of ethanol and less than 20-5% by weight of propylene glycol.

The "blood plasma melatonin concentration" can be a mean value measured in a study of the type described in Example 4 below. Such studies or trials are well known to those skilled in the art.

When used in this specification, the term "single or simultaneous intranasal administration" encompasses both the administration of a single dose or dose form, such as a single insufflation of a powder, or a single application of a spray, and the contemporaneous administration of a plurality of such doses or dose forms, (for example, the administration of two squirts of a spray or powder insufflations, one in each nostril).

It has also been found that glycerol and cyclodextrin, when employed in nasal compositions containing melatonin, do not exhibit the unwanted toxic and adverse effects previously noted with the use of (poly)alcohols. It has further been found that cyclodextrin accelerates the absorption of melatonin in the nasal mucosa.

The powdered pharmaceutical compositions in accordance with the first aspect of the invention may include cyclodextrin, and preferably 3-cyclodextrin.

Such compositions are pharmaceutically acceptable because they do not cause the serious local irritation, pain and toxic side effects caused by the (poly) alcohols used in previously proposed compositions.

In addition to powder, nasal compositions in accordance with the invention may be administered as a nasal spray, drop, solution, suspension, gel, ointment or cream. The composition may also be administered using a nasal tampon or a nasal sponge. The composition is preferably administered however, in the form of an aqueous composition or a dry powder. The aqueous composition may be an aqueous solution, but can be a suspension, or a gel.

-4- When taken as an aqueous composition suitable compositions can be obtained with or without glycerol as an additive. Glycerol allows aqueous compositions containing relatively high amounts of melatonin, which do not exert toxicity towards the epithelial membrane, and do not lead to irritation of the nasal mucosa. An additional advantage of the use of glycerol is the preservative properties thereof, leading to stable solutions.

As mentioned above, when taken as a powder, the composition preferably contains cyclodextrin and more preferably a melatonin-cyclodextrin complex to obtain optimum onset times.

Melatonin-cyclodextrin complexes, however, can be employed in any embodiment of the present invention.

The term cyclodextrin refers to cyclodextrins such as a-cyclodextrin, pcyclodextrin, -y-cyclodextrin, and derivatives thereof, such as methylated or alkylated cyclodextrins. Examples are methylated -cyclodextrin, hydroxypropyl- and hydroxyethyl-cyclodextrin, (di)glucosyl- or (di)maltosyl-cyclodextrins, carboxymethyl- or sulfoalkylether cyclodextrins, s such as sulfobutylether-0-cyclodextrin. The preferred cyclodextrin is methylated 0-cyclodextrin, or more preferred 0-cyclodextrin.

When a complex of melatonin and cyclodextrin is used, and additionally glycerol is used as a further additive, the ratio of glycerol:cyclodextrin may i0 vary between 1:5 and 500:1 by weight, and preferably between 1:1 and 50:1 by weight.

Pharmaceutical compositions in accordance with the present invention can be formulated to provide a single melatonin dose of between 10Cg and Img ij and, preferably, of between 0.8, 0.6, 0.5 or 0.4mg and 0.2, 0.15, 0.1 or 0.05mg. When used in such low doses, compositions in accordance with the invention will still provide a sufficiently high peak melatonin blood plasma concentration sufficiently soon after administration to be effective in the treatment of human disease, particularly insomnia, or in causing drowsiness or sleep in humans. Thus, the present invention allows effective melatonin blood plasma concentrations to be achieved even when using extremely low melatonin doses.

In preferred embodiments, pharmaceutical compositions in accordance with the invention comprise aqueous compositions of 0.1 to 10 mg/ml of melatonin, and one or more of 1 to 250 mg/ml of cyciodextrin and 5 to by volume of glycerol, or powdered compositions of 0.5 to 50% by weight of melatonin, and 2.5 to 90% by weight of a cyclodextin. Such a nasal powder can comprise daily doses or dosage units of 0.01 to 1 mg oi 3o melatonin, and preferably of about 0.1 to 0.8 mg of melatonin, for sleep induction in man.

In a second aspect, the present invention provides a pharmaceutical dose or dose form comprising sufficieit of a pharmaceutical composition in accordance with the first or second aspect of the invention to contain up to 1mg, 0.8mg, 0.6mg, 0.5mg or 0.4mg of melatonin and, preferably, at least O.Olmg, 0.05mg, 0.1mg, 0.15mg or 0.2mg of melatonin. Said pharmaceutical dose can be in any of the aforementioned forms, including a measured quantity of a liquid for application as a spray or in drops, a spray or drop of liquid, or a powder.

o0 A pharmaceutical dose or dose unit in accordance with the invention preferably contains an additive selected from glycerol, cyclodextrin, and mixtures thereof, and will give effective sleep-induction in man.

In a further aspect, the present invention provides a pharmaceutical is product, comprising apparatus for intranasally administering a pharmaceutical dose or dose form in accordance with the third aspect of the invention, and a pharmaceutical composition in accordance with the first or second aspect of the invention. The apparatus can comprise a reservoir and means for expelling the pharmaceutical dose in the form of a spray, wherein a quantity of the pharmaceutical composition is contained within the reservoir. In an embodiment, the apparatus comprises a pump spray device in which the means for expelling a dose comprises a metering pump. In an alternative embodiment, the apparatus comprises a pressurized spray device, in which the means for expelling a dose comprises a metering valve and the pharmaceutical composition further comprises a conventional propellant. Suitable propellants include one or mixture of chlorofiuorocarbons, such as dichlorodifluoromethane, and che more recent and preferred hydrofluorocarbons, such as i,1,1,2-tetrafluoroethane

(HFC-

1 3 4a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227). Suitable pressurized Jo spray devices are well known in the art and include those disclosed in, inter alia, WO92/11190, US-A-4819834, US-A-4407481 and W097/09034, when adapted for producing a nasal spray, rather than an aerosol for inhalation, 7or a sublingual spray. Suitable nasal pump spray devices include the and VP100 models available from Valois S.A. in Marly Le Roi, France and the 50, 70 and 100l1 nasal pump sprays available from Pfeiffer GmbH in Radolfzell, Germany, although other models and sizes can be s employed. In the aforementioned embodiments, a pharmaceutical dose or dose unit in accordance with the invention can be present within the metering chamber of the metering pump or valve.

Pharmaceutical compositions, doses or products in accordance with the o1 present invention are useful in the treatment of human diseases known to be responsive to melatonin, including insomnia, and for inducing drowsiness or sleep in human subjects. They also provide a fast onset time and are suitable for intranasal use. Although not wishing to be bound by any particular theory, it is considered that the capacity of compositions in ii accordance with the present invention for providing high blood plasma melatonin concentrations very rapidly after administration, on the basis of significantly reduced doses of melatonin, leads to their enhanced efficacy and reduces the likelihood of any unwanted side-effects being caused.

2o In a yet further aspect of the present invention, there is provided the use of melatonin for the preparation of a pharmaceutical composition, dose or product in accordance with any previously described aspect of the invention, for treating insomnia, or inducing sleep or drowsiness. Use of a pharmaceutical composition, dose or product in accordance with any previous aspect of the invention, for the preparation of a medicament for treating insomnia, or inducing sleep or drowsiness, is also encompassed by the present invention.

The invention also comprises methods for treating disease, including 3-o insomnia, and for inducing sleep in humans by intranasally administering a pharmaceutical composition in accordance with the first or second aspect of the invention or a pharmaceutical dose in accordance with the third aspect 8 of the invention. The preferred unit dose is 0.01 to 1 mg of melatonin, and more preferably is 0.1 to 0.8 mg of melatonin.

Pharmaceutically suitable auxiliaries and liquids, such as those described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture) can be included in compositions of the present invention. Such compositions can be processed into vials or containers, for instance, to provide a spray as aforesaid. For making dose units, any pharmaceutically acceptable additives or excipients which do not interfere with the function of the active compound can be used.

To further improve the absorption of melatonin from the nasal is composition, nasal absorption enhancers, which are known in the art, may be added. Also viscosity enhancers may be added, for example natural gums, cellulose derivatives such as hydroxypropylmethyl cellulose or methyl cellulose, acrylic polymers (carbopol), and vinyl polymers (polyvinylpyrrolidone). Other conventional pharmaceutically acceptable excipients may also be added, such as preservatives, surfactants, colorants, co-solvents, adhesives, anti-oxidants, buffers, and agents to adjust the pH and osmolarity.

Nasal powder compositions can be made by mixing the active ingredients and the excipients, both possessing the desired particle size. Other methods to make a suitable powder formulation are the preparation of a solution of active ingredients and excipients, followed by precipitation, filtration, and pulverization, or followed by removal of the solvent by freeze-drying, followed by pulverization of the powder to the desired particle size. The 2o final step can be sieving to obtain panicles with a size of less than 100 Am in diameter, preferably between 50 and 100 jm in diameter. Powders can be administered using a nasal insufflator, a jet-spray, or any other conventional device known in the art.

The invention is further illustrated by the following examples.

Example 1 A solution was prepared from the following ingredients: melatonin 50 mg 1:1 molar complex of melatonin and f-cyclodextrin 900 mg o1 sodium chloride 900 mg benzalkonium chloride 10 mg sodium EDTA 100 mg sterilized water up to 100 ml i The solution was filtered, stored at 5 0 C for 24 h, and filtered again. The solution was then packaged into vials or pump spray devices, each containing 10 ml of the solution and arranged to provide 100 doses of 0.2 mg of melatonin.

Example 2 In a reaction vessel, 200 mg of melatonin and 900 mg of sodium chloride were agitated at room temperature in a mixture of 30 ml of glycerol and sufficient water to make the total volume up to 100 ml, until a clear solution was obtained. The solution was filtered, stored at 50C for 24 h, and filtered again. This solution can be packaged into vials or containers as discussed in Example 1 and each 10 ml aliquot can provide 100 dose units of 0.

2 mg melatonin.

Example 3 A solution was prepared containing 200 mg of melatonin, 1.2 g of a complex of 200 mg of melatonin and 1 g of 0-cyclodextrin, 5 g of sorbitol, s 10 ml of glycerol, and 10 mg of benzalkonium chloride in sufficient water to make the total volume up to 100 ml. The solution was filtered, stored at for 24 h, and filtered again. This solution can be packaged into vials or containers as discussed in Example 1 and, for instance, a container filled with 10 ml of the solution will contain 100 doses of 0.4 mg of melatonin.

Example 4 An open randomized, four treatment (treatments A, B, C and D below), cross-over study involving 8 healthy male volunteers was carried out.

Before drug administration, the subjects were fasted overnight for at least z 10 hours. The administered formulations were as follows:- A: 100 water, intranasal (placebo); B: 200g of melatonin in a 100,1 dose of an aqueous solution prepared by the method of Example 1, administered intranasally to one nostril; C: 4 00g of melatonin in two 1001 doses of an aqueous solution prepared by the method of Example 1, each administered intranasally to a separate nostril; D: 2.5mg of melatonin in an immediate release oral tablet taken with 1COmI of water.

After administration, blood plasma melatonin concenrrarions were 11 measured in the volunteers by radioimmunoassay and the results are set out in Tables 1, 2 and 3. The results set out in Table 1 are also illustrated graphically in Figure 1 in which MLT stands for melatonin and N is the number of volunteers in the study.

It was noted that all treatments, both nasal and oral, were safe and well tolerated with no adverse events being reported.

These results show that nasally administered melatonin was absorbed io extremely rapidly and that peak plasma concentrations were proportional for the 0.2 and 0.4mg nasal doses and took place at a of less than 10 minutes after administration, compared to a of 1.5 hours for the orally administered 2 .5mg melatonin tablets (see Table 2).

I About the same amount of melatonin was absorbed from the 0.2mg nasal dose as was absorbed from the 2.5mg oral dose and the amount of melatonin absorbed from the 0.4mg nasal dose was found to be proportional to that absorbed from the 0.2mg nasal dose.

Although the 0.2 and 0.4mg nasal doses were much lower than the oral dose, they produced peak plasma concentrations (Cm) which were about 5 and 11 times, respectively, higher than that resulting from the oral dose (see Table 3).

The peak melatonin plasma concentrations noted were unexpectedly high and achieved in a surprisingly short period of time. These properties mean that compositions in accordance with the present invention are surprisingly effective and useful in treating insomnia, or causing drowsiness or sleep, when compared to previously known oral compositions. The high peak Jo levels provide an enhanced effect and the rapid onset means that compositions in accordance with the present invention can be taken immediately before their effect is required, rather than 1-2 hours 12 beforehand. Moreover, the total dose required to provide a useful effect is much lower than previously required. Accordingly, compositions in accordance with the present invention are not only more effective than previously proposed oral compositions, but they can achieve their effect at lower dose levels than those previously proposed.

Table I Plasma mclatonin concentrations (mean +SD.

TI1ME TREATMENT A TREATMENT B TREATMENT C TREATMENT

D

AFTER

0 hours min min min 20 min min I hours hours 2 hours D, 2.5 hours 3 hours 4 hours hours 6 hours 8 hours [pg/mI] [pg/mi] [pg/mi] [pg/mi] 12.6 12.6 12.3 12.1 11.6 13.8 11.6 13.5 12.0 11.8 15.3 13.1 12.0 11.7 12.9 8.31 8.63 8.10 7.91 7.60 10.7 7.61 6.93 8.25 7.94 7.61 5.69 8.29 8.03 8.62 14.1 ±8.23 5399 ±1154 3747 ±906 2537 ±628 1916 ±472 1037 ±437 637 ±369 455 ±265 332 ±236 238 ±225 156 ±117 101 ±78.4 43.1 ±32.4 29.7 ±13.4 23.6 ±6.68 17.9 ±5.37 11436 ±3150 7515 ±1944 5293 ±2149 3912 ±1465 2259 ±783 1460 ±601 941 ±508 574 ±429 418 ±397 293 ±246 153 ±106 70.6 ±45.5 43.4 ±19.9 31.2 ±9.06 16.1 ±4.00 37.0 ±20.1 130 ±103 277 ±281 403 ±540 906 ±1346 1266 ±1741 1523 ±1768 1438 ±1318 981 ±874 629 ±485 230 ±157 101 ±108 60.3 ±64.8 37.5 ±18.8 Table 2 PHAl RAM COK!NE77CS Pharmacokinctic parameters after singic-dose administration of treatments A, B, C and D (mean :t SD) PARAMETERS TREATMENT A TREATMENT B TREATMENT C TREATMENT D AUC pg.li/ml 115 ±49.6 2796 ±1000 5725 ±2015 3852 ±3727 Gina 1 pg/mi 18.5 ±7.8 5169 ±1305 11437 ±3151 1790 ±1798 tmax h 2.66 ±2.54 0.10 ±0.04 0.08 ±0.00 1.56 ±0.42 t h 1.04 0.30 1.00 0.20 0.90 0.24 AUC Area under the plasma concentration time curve peak plasma concentration (average value using "best fit" curve) tm time to reach the C..

t I/ half-life of elimination TABLE 3 R4 710 ES11MA 7ES A AD 9M%-CONFIENCE iNER VAILS COMPARISON PARAMETER N RATIO ESTIMATE 90% Ci C to B to Cto D B to D

AUG

Cmax

AUG

Cm

AUG

r 2.03 2.20 2.34 11.0 1.10-3.76 1.20-4.04 1.26-4.33 6.01-20.3 0.62-2. 13 Al 2.73-9.23 N number of volunteers in the survey.

Claims (18)

1. A powdered pharmaceutical composition when used for intranasal administration, the composition comprising melatonin and a pharmaceutically acceptable excipient, characterised by being effective to cause the blood plasma concentration in a human adult, receiving an amount of melatonin in the range of 50-1000 ig and in a single dose or simultaneous intranasal administration of said composition, to reach at least Xpg/ml, within 30 minutes of said administration, wherein X is equal to 5 times the amount of melatonin, expressed in in said single or simultaneous administration.

2. A powdered pharmaceutical composition as claimed in claim 1, wherein X is equal to 10, 15, 20 or 25 times the amount of melatonin, expressed in ig, in a single or simultaneous administration.

3. A powdered pharmaceutical composition as claimed in claim 1, effective to cause the blood plasma melatonin concentration in a human adult, receiving 200 pg of melatonin in a single or simultaneous administration of said composition, to reach at least 1000 pg/ml within 30 minutes of administration.

4. A powdered pharmaceutical composition as claimed in claim 3, wherein the melatonin concentration reaches at least 2000, 3000, 4000 or 5000 pg/ml within 30 minutes of administration.

A powdered pharmaceutical composition as claimed in any one of claims 1-4, wherein said melatonin concentration is reached within 15, 10, 8, 7, 6 or minutes of administration.

6. A powdered pharmaceutical composition as claimed in any one of claims wherein the additive is a cyclodextrin, or glycerol, or an admixture of a cyclodextrin and glycerol.

7. A powdered pharmaceutical composition as claimed in claim 6 wherein the cyclodextrin is 3-cyclodextrin.

8. A pharmaceutical dose comprising sufficient of a powdered pharmaceutical composition as claimed in any one of claims 1-7 to contain up to 1mg, 0.8mg, 0.6mg, 0.5mg or 0.4mg of melatonin.

9. A pharmaceutical dose as claimed in claim 8 and comprising at least 0.01mg, 0.05mg, 0.1mg, 0.15mg or 0.2mg of melatonin.

A pharmaceutical product comprising apparatus for intranasally administering a pharmaceutical dose as claimed in claim 8 or claim 9, and a pharmaceutical composition as claimed in any one of claims 1-7.

11. A pharmaceutical product as claimed in claim 10, wherein the apparatus comprises a reservoir and a means for expelling the pharmaceutical dose in the form of a spray, wherein a quantity of the pharmaceutical composition is contained within the reservoir.

12. A pharmaceutical product as claimed in claim 11, comprising a pump spray device, wherein the means for expelling a dose comprises a metering pump.

13. A pharmaceutical product as claimed in claim 11, comprising a pressurised spray device, wherein the means for expelling a dose comprises a metering valve and the pharmaceutical composition further comprises a propellant.

14. A pharmaceutical composition, dose or product as claimed in any one of the preceding claims, for treating insomnia or inducing drowsiness or sleep.

Use of melatonin for the preparation of a powdered pharmaceutical composition, dose or product as claimed in any one of claims 1 to 13 for treating insomnia or inducing sleep or drowsiness.

16. Use of a powdered pharmaceutical composition, dose or product as claimed in any one of claims 1-13, for the preparation of a medicament for treating insomnia or, inducing sleep or drowsiness.

17. A method of inducing drowsiness or sleep in a healthy individual comprising administering to that individual a powdered pharmaceutical composition or dose as claimed in any one of claims 1-9.

18. A method of treating a human in need of melatonin therapy, or of inducing drowsiness or sleep in a human, comprising the intranasal administration to said human of a powdered pharmaceutical composition as claimed in any one of claims 1-7, a pharmaceutical dose as claimed in claim 8 or claim 9, or a pharmaceutical product as claimed in any one of claims 10-13. -18- Dated this eleventh day of June 2002 Franciscus W H M Merkus Patent Attorneys for the Applicant: F B RICE CO