KR20050115276A - Novel compositions - Google Patents

Abstract

This invention relates to formulations of fentanyl, especially pump spray formulations suitable for sublingual delivery.

Description

New composition {NOVEL COMPOSITIONS}

The present invention relates to formulations of fentanyl, in particular pump spray formulations suitable for sublingual delivery.

Fentanyl is an anesthetic alkaloid, which has been used for years as an anesthetic and analgesic for palliative care, especially for severe pain. While undoubtedly effective in alleviating pain, and especially in treating refractive pain in other treatments, there are many clinical management problems associated with the use of fentanyl in treatment.

The most serious of these problems is the potential for severe side effects of fentanyl. It is often much more potent than known anesthetics and therefore it is necessary to ensure that it is used within the therapeutically effective range established and to monitor patients for evidence of self-administration more than the recommended dose. Fentanyl overdose can result in many undesirable and really life-threatening, mainly side effects of hypopentilation and inhibition of respiratory function.

Because of the nature of the condition being treated, it is highly desirable that onset of analgesia occur immediately after dosing as long as it is compatible with safety parameters. Moreover, retardation in the manifestation of action may induce the patient to take another dose, with the inevitable risk of overdose, as already described above.

The route of administration of many drugs can be associated with the rapid onset of action. For example, international patent application WO90 / 07333 (Riker Labs) describes an aerosol formulation of fentanyl, which is applied for inhalation. Riker's formulations, however, suffer from disadvantages such as the use of hydrofluorocarbon propellants and delivery affected by metered dose inhalers. Disadvantages in the former case include high rates resulting in a 'bounce back' of the administration before the mouth, cold sensation and the risk of inhalation; for the latter, respiration and actuation by the patient Includes careful coordination of actions. When metered dose inhalers are used, a significant proportion of the delivered dose tends to impact the back of the throat from where it is swallowed rather than finding its way into the passage of the bronchus. Thus, the pharmacology of dosing may be unpredictable or characterized as a bi-phasic profile due to poor bioavailability after oral administration (due to rapid initial expression and oral absorption of fentanyl as a result of inhaled doses). Slower, late effect). Moreover, the preparation of bulk formulations involves the preparation of large amounts of pressurized volatile propellants containing potent anesthetic analgesics. Therefore, the precautions required to ensure safe manufacturing are burdensome and expensive.

WO95 / 31182 (Aradigm Corp) describes a solution formulation of fentanyl in an aerosol propellant intended for administration to a patient by the pulmonary route.

WO01 / 97780 (Pharmasol Ltd) describes a solution formulation of fentanyl free base in a propellant, typically HFA134a, for sublingual aerosol administration.

WO00 / 47203 (MQS Inc) describes formulations of fentanyl citrate for oral administration with oral absorption enhancers.

Such conventional fentanyl formulations utilize propellants and also experience the drawbacks described above.

Aqueous formulations of fentanyl for intranasal administration using water and phosphate buffers are described (Peach, MJ, Lim, CB, Banks, SL, Rucklidge, MWM & Doherty, DA (2003) Anaesthesia 58 (8), 740-744 and Lim et al (2003) J Pharm Practice Research 33, 59-63), such formulations may experience the problem of nasal irritation associated with medium for long term use through this route, which is undesirable. Weinberg et al (1988) Clin Pharmacol Therap 44 335-342 discloses a formulation of fentanyl with water and phosphate buffer for sublingual administration but this formulation is not supported for use as a spray.

It is well known that the application of a carefully selected agent to the sublingual mucosa provides a route of administration that allows for the rapid delivery of the agent to the blood stream, with a rapid effect manifestation. Many methods of administering the composition sublingually are known. For example, tablets or liquids may be placed under the tongue before swallowing. Another method is spray delivery. Among these various sublingual administrations, do not include putting the composition under the tongue, such as lozenge, for an extended period of time, and reduce the amount of substance to be swallowed (and via the gastrointestinal tract). Spray delivery is preferred because it may enter the bloodstream in a delayed manner). Pharmaceutical compositions, such as fentanyl lozenge tablets, result in increased saliva secretion, which promotes unwanted swallowing of the pharmaceutical substance. Spray delivery, which has a small volume and the ability to target the sublingual mucosa, generally alleviates this. Fentanyl-free spray formulations of fentanyl applied for sublingual administration have not yet been known.

1 is a flow chart showing a first step of a method of preparing a formulation comprising 400 μg of fentanyl.

2 is a flow chart showing a second step of the method.

It is an object of the present invention to provide formulations which avoid or alleviate some or all of the above mentioned disadvantages.

Thus according to a first aspect according to the invention there is provided a pharmaceutical composition, which is a partially pressurized liquid spray formulation comprising:

(a) Fentanyl or a pharmaceutically acceptable salt thereof

(b) water as carrier: and

(c) A polar organic solvent in an amount sufficient to enhance the solubility of fentanyl or a pharmaceutically acceptable salt thereof in water.

Formulations of the present invention are preferably administered sublingually as a spray. The formulation is well tolerated when administered to sensitive sublingual mucosa, and sublingual spray administration will result in rapid manifestation of the therapeutic effect of fentanyl.

The formulation of the invention preferably also does not contain any propellant.

The best of these formulations is the fact that they are based on water, thereby avoiding the problems associated with using pressurized hydrofluorocarbon propellants such as those mentioned above. Formulations are partially pressurized and include volatile chlorofluorocarbons (eg propellant 12), volatile hydrofluoroalkanes (eg 1,1,1,2-tetrafluoroethane and 1,1,1, It does not include propellants such as 2,3,3,3-heptafluoro-n-propane and volatile alkanes (eg propane, butane) and other materials having significant vapor pressure at ambient temperature and pressure.

In one embodiment of the invention, the formulation is a solution rather than a suspension. It is possible to spray the suspension, but the fact that most of the suspension precipitates means that the amount of active agent included in the dose administered will vary and this may be very undesirable. The precipitation effect of the suspension can be reduced to some extent by shaking the composition before spraying, but some suspensions can precipitate very quickly, so there is still a possibility for changes in active agent content between doses.

Moreover, the formulations of the present invention are characterized by good long term physical and chemical stability.

Fentanyl can be used in the form of a physiologically acceptable salt and can be dissolved in water with a polar organic solvent. Examples of suitable salts are hydrochloride , chloride , sulphate, tartrate and citrate. Preferably fentanyl is used as the free base.

Preferably fentanyl or a physiologically acceptable salt thereof will be employed in the formulation at a concentration of 0.1 mg / ml-10 mg / ml, preferably 0.5 mg / ml-4.4 mg / ml (weight is the weight of fentanyl free base). Is indicated).

Examples of polar organic solvents that can be used to enhance the solubility of fentanyl or its physiologically acceptable salts in water include: lower alcohols such as ethanol (eg C _2-4 alcohols); Lower polyols (such as C _2-4 polyols) such as glycerol and propylene glycol; And polyethylene glycols such as PEG200 and PEG400.

Mixtures of the above materials can be used. Preferred polar organic solvents are ethanol.

In another embodiment of the invention, the formulation does not comprise ethanol. Indeed, the formulation may be substantially free or completely free of any alcohol.

If the composition is free of alcohol, the carrier used is preferably a polyol. Preferred polyols include propylene glycol and glycerol.

Generally speaking, it will be desirable to use the minimum amount of polar organic solvent necessary to properly dissolve fentanyl, or its physiologically acceptable salts, so that fentanyl remains in solution under conditions of likely use or exposure.

The concentration of the polar organic solvent is preferably in the range of 6-50%, more preferably 20-45%, in particular 35-42%.

Preferably the water meets USP (US Pharmacopoeia), EP (European Pharmacopoeia) "purified water" criteria.

It has also been found that the properties of the claimed formulations can be improved by including many additional formulation components therein.

Therefore, in one embodiment of the invention, the water in the formulation is in the form of an aqueous buffer solution. The buffer is applied to stabilize the pH of the formulation to pH 7.4-8.5, preferably pH 8.0-8.5, more preferably pH 8.1-8.3, or about 8.2. At higher pH values, we found evidence that the bioavailability of the formulation improved with respect to lower pH values (eg near pH 6). Examples of buffer systems include sodium acetate / acetic acid, Ammonium acetate / disodium edetate, boric acid / sodium hydroxide, orthophosphoric acid / sodium hydroxide, sodium hydrogen carbonate / sodium carbonate, disodium hydrogen orthophosphate / citric acid (taken from British Pharmacopoeia). Preferred is the use of citrate buffers, for example buffers include citric acid , sodium citrate and sodium hydroxide.

The concentration of the aqueous component (water or more preferably aqueous buffer solution) of the formulation of the invention is preferably 50-94%, more preferably 55-80%, and especially 58-65%.

It may be desirable to include one or more of the following ingredients in the formulation.

1) Sweeteners, flavors or taste masking agents (to improve the patient's water solubility) such as vanilla, pineapple extract, menthol, saccharin and sodium saccharin.

2) Moisturizers (to improve patient comfort and overcome the tendency to dry ethanol and other organic solvents) such as pineapple extract, lanolin, polypropylene glycol, and polyethylene glycol.

3) penetration enhancers (to enhance the therapeutic effect), for example menthol.

4) mucoadhesives (to increase the residence time in the mucosa), for example carboxyvinyl polymers, chitosan, polyacrylic acid, gelatin and polyvinyl pyrrolidone.

5) Preservatives (to improve long-term resistance to microbial contamination), for example ethanol, sodium metabisulfite, benzalkonium chloride and nipas.

6) Antioxidants such as alkyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, tocopherol, ascorbic acid and sodium metabisulfite.

7) Anionic surfactants such as magnesium stearate, sodium cetostearyl sulfate, sodium lauryl sulfate, sulfated caster oil, sodium oleate, sodium stearyl fumarate and sodium tetradecyl sulfate.

8) Nonionic surfactants such as glyceryl monostearate, macrogol cetostearyl ether, poloxamer, polyoxyl stearate, polysorbate, sorbitan esters, sucrose esters, tyloxapol, propylene glycol monostea Latex, quillaia, polyoxyl castor oil, nonoxynols, lecithin and derivatives, oleic acid and derivatives, oleyl alcohol and derivatives.

9) Blowing agents such as alginic acid and salts, propylene glycol alginate, sodium lauryl sulfate, sodium cetostearyl sulfate, carbomers, hydroxyethylcellulose.

Some of the components proposed above may already be included in the compositions of the present invention for other purposes. Suitable humectants include, for example, polar organic solvents such as glycols, in particular propylene glycol, and liquid polyethylene glycols, glycerol, methylcellulose, hypromellose, hydroxypropylcellulose, and many other substituted celluloses. Include.

A versatile component that improves acceptability and other properties of the formulation is menthol. In addition to framing the formulation, menthol also has a moisturizing effect. It also has an effect as a penetration enhancer. Preferably menthol is used in the concentration range of 0.25% to 7.5%.

One particular advantage of menthol is that it is compatible with fentanyl in spray formulations, unlike peppermint oil (menthol is a component) that degrades fentanyl.

In an embodiment of the invention, the formulation contains a sweetener. Preferred sweeteners are their physiologically acceptable salts such as saccharin or saccharin sodium. Preferably the concentration of sodium saccharin or its physiologically acceptable salt is about 0.1-0.5%, for example about 0.28%.

Preferably the formulation contains saccharin. Surprisingly, we have found that the long-term stability of formulations containing saccharin is better than the stability of formulations containing saccharin sodium.

It has been found that it is generally not necessary to include a preservative in the formulation when ethanol is present because of its preservation properties.

Formulations of the invention are useful for the treatment of pain and pain. In another aspect of the invention, the formulation according to the first aspect of the invention is provided for use in the treatment of severe pain relief. In another aspect of the invention there is provided the use of a formulation according to the invention in the manufacture of a medicament for the treatment of pain or pain. In one embodiment, a therapeutically effective amount of a formulation for the treatment of pain according to the invention is used.

The formulation according to the invention is preferably packaged as a bulk solution containing a plurality of doses in a pump spray system comprising a sealed container equipped with a metering pump. Thus, as one aspect of the present invention we provide a sealed container containing a plurality of doses of a formulation according to the present invention. The container will preferably contain 20 to 200 doses. Examples of containers are those made of plastic, glass and metal (eg aluminum), but glass containers are preferred. Glass containers have the advantage of being able to see the contents of the container (for example, it is possible to visually measure when the contents are almost consumed). Moreover, glass containers are less susceptible to tampering, an important consideration for anesthetics.

In another embodiment, a single or multiple use device comprising a single or multiple doses of a formulation of the invention is realized.

Preferably the glass container will be coated on the outside with a suitably molded plastic film to prevent shattering. For example, the film can be polypropylene. The material may be colored and may contain ultraviolet (UV) absorbers. Optionally, the interior of the container can be coated to improve the stability of the product. Coatings include polymers and lacquers, but silicon dioxide can also be used for non-reactive coatings inside containers.

Another aspect of the invention is a metered dose dosing system comprising a sealed container containing a formulation of the invention, equipped with a metering pump, an actuator and a channelization device. The metered dose dosage system is preferably applied for sublingual administration.

Suitable metering pumps include those adapted for dosing with the container in the vertical or reverse direction. The metering chamber is preferably applied for dosing with the container in the vertical direction because it facilitates sublingual administration. The metering chamber will thus communicate with the bulk formulation by deep-tube.

  Examples of metering pumps are those manufactured by Valois and are exemplified in International Patent Application WO01 / 66089.

The metering pump is preferably non-outlet with a deep tube. Such non-outlet metering pumps may have a metering chamber capacity of, for example, 100 μl. The material of the structure includes polypropylene and polyethylene. For example, suitable sealing materials that are suitable thermoplastic crimp gaskets will be used for the purpose. In addition, suitable aluminum ferrules intentionally designed for crimping onto glass containers may be used as appropriate. Appropriate grades of stainless steel springs will preferably be employed.

Preferably the manipulator will be designed to deliver a potent dose sublingually. The packaging can be further enhanced by mounting a locking system to promote compliance by the patient.

Typically one to four times Treatment is by sublingual administration of manipulation, for example one or two manipulations from a spray pump. Another advantage of sublingual spray delivery is the ability of the patient to titrate easily in one or two doses as required by a single operation. This is not the case for other forms of dose delivery (patches, lozenges, tablets, suppositories).

 One of the possible methods for producing any formulation and filled container according to the invention is shown in the drawings for purposes of illustration.

Other formulations of the invention can be prepared by similar methods or by methods known to those skilled in the art.

The weight percentage values given here are expressed as w / w.

The formulations and products of the present invention have better physical and chemical stability, are more environmentally friendly, more convenient or safer to administer to patients, more convenient or safer to manufacture, more economical to manufacture, Or has other advantages over conventional formulations and products.

The invention will now be illustrated with reference to the following examples:

Normal

When used, the citrate buffer contained:

Citric acid 2.0%

Sodium Citrate 1.0%

Sodium hydroxide 1.0%

Water: until it reaches 100%

pH 8.2 (adjusted with sodium hydroxide).

Example 1

Formulation (per container)

Fentanyl Base 0.0280g

Saccharin 0.0177 g

Absolute Ethanol 2.8336g

Menthol 0.0531g

Citrate buffer solution 4.1516g

Target dose is 400 μg per operation.

Example 2

Formulation (per container)

Fentanyl Base 0.0280g

Saccharin sodium 0.0198 g (0.0177 g saccharin and equivalent)

Pure Ethanol 2.8336g

Menthol 0.0531g

Citrate buffer solution 4.1516g

The target dose is 400 μg per 100 μl of operation.

Example 3

Formulation (per container)

Fentanyl Base 0.0280g

Saccharin 0.0177 g

Pure Ethanol 2.8336g

Citrate buffer 4.2047 g

The target dose is 400 μg per 100 μl of operation.

Example 4

Formulation (per container)

Fentanyl Base 0.0280g

Saccharin sodium 0.0198 g (0.0177 g saccharin and equivalent)

Pure Ethanol 2.8336g

4.2026 g of water

The target dose is 400 μg per 100 μl of operation.

Example 5

Formulation (per container)

Fentanyl base 0.0140 g

Saccharin sodium 0.0198 g (0.0177 g saccharin and equivalent)

Pure Ethanol 2.8336g

Menthol 0.0531g

Citrate buffer 4.1656g

The target dose is 200 μg per 100 μl of operation.

Formulation Package

Example Formulations may be packaged in suitably coated glass containers and equipped with appropriate non-outlet metered dose pumps. Appropriate manipulators may be equipped for sublingual delivery.

Test data

The formulation of Example 1 was tested as follows.

The unit was placed in a stability reservoir at 5 ° C., 25 ° C./60% RH, 30 ° C./65% RH and 40 ° C./75% RH. Three repetitions were evaluated for each test.

a) appearance (including transparency).

   Observations were made and results recorded.

b) the average weight of the dose released (fire weight)

   Each unit will be weighed before and after the test spray. From these measurements, the average shot weight will be calculated by other calculations.

c) pH

   pH is measured on a single unit at each time point in each condition. The unit is opened under controlled conditions and pH measured by the use of a pH meter.

d) decomposition products

   Samples of the formulation were taken from each unit and tested for degradation products by HPLC analysis. The results were reported as 'none (ND)', <0.1% (unconfirmed) or as a percentage of identified degradation.

the results are as follow:

The same test was done on the formulation of Example 2 with the following results:

Condition A: 2-8 ℃, ambient humidity

Condition B: 25 ° C., 60% relative humidity

Condition C: 30 ° C, 60% relative humidity

Condition D: 40 ° C, 75% relative humidity

Appearance: All samples were clear and colorless without any particles.

Firing weight: All samples were in target.

pH: stable (8.2-8.3).

Moisture Content: Acceptable.

Decomposition products A and B: Nothing was detected.

From the test results, it was concluded that the tested formulations of the present invention exhibited excellent physical and chemical stability.

Claims (26)

(a) fentanyl or a pharmaceutically acceptable salt thereof; (b) water as a carrier; And (c) A pharmaceutical liquid spray formulation comprising fentanyl or a pharmaceutically acceptable salt thereof in an amount sufficient to enhance solubility in water. The formulation of claim 1, wherein the fentanyl is present as a free base. The formulation of claim 1, wherein the formulation is partially pressurized. The formulation according to any one of claims 1 to 3, wherein the fentanyl, or pharmaceutically acceptable salt thereof, is present at a concentration of 0.1-10 mg / ml. The formulation according to claim 1, wherein the polar organic solvent is selected from ethanol, propylene glycol, glycerol or polyethylene glycol and mixtures thereof. The formulation of claim 5, wherein the polar organic solvent is ethanol. The formulation of claim 1, wherein the polar organic solvent is present in an amount of 6-50% w / w. The formulation of claim 7 wherein said polar organic solvent is present in an amount of 35-42% w / w. The method of claim 1, wherein the formulation is buffered. Formulation. The formulation of claim 9, wherein the formulation is buffered with citrate buffer. The formulation of claim 1, wherein the formulation has a pH between 7.4 and 8.5. The formulation of claim 11, wherein the formulation has a pH of about 8.2. The formulation according to any one of claims 1 to 12, which contains a sweetener. The formulation of claim 13, wherein the sweetener is saccharin. The formulation of claim 13, wherein the sweetener is saccharin sodium. The formulation according to any one of claims 1 to 15, which contains menthol. 17. The formulation according to any one of claims 1 to 16 for sublingual administration as a spray. The formulation according to claim 1, for use as a method of treating pain or as analgesic. The formulation of claim 18, wherein the formulation is administered sublingually as a spray. Use of a formulation according to any one of claims 1 to 17 in the manufacture of a medicament for the treatment of pain or pain. The use of claim 20, wherein the formulation is administered sublingually as a spray. A sealed container containing a plurality of doses of the formulation according to any one of claims 1 to 17. 23. The container of claim 22, wherein the container is made of glass. A metered dose dosage system comprising a sealed container according to claim 22 or 23 equipped with a metering pump, manipulator and channeling device. The metered dose dosage system of claim 24, comprising a metering chamber adapted for administration with the container in a vertical direction, wherein the metering chamber is adapted to communicate with the formulation by a deep-tube. The metered dose dosage system of claim 24 or 25, which has been applied for sublingual administration of the formulation as a spray.