Nasal formulations and a process for preparation thereof.

Process for the preparation of pharmaceutical compositions for nasal administration containing phospholipids

The present invention relates to novel pharmaceutical preparations adopted for intranasal administration and a process for their preparation.

Background of the invention

While non-invasive medication, such as for example oral or rectal administration of a drug is undoubtedly the most convenient for a patient, parenteral administration of the drug is usually seen as the most effective. In particular, drugs that are inactivated or poorly absorbed in the gastrointestinal tract and drugs that undergo hepatic metabolism in an extensive first phase followed by oral administration are usually administered parenterally.

Of course there are drawbacks associated with parenteral drug administration such as the need for sterile utensils, pain and irritation caused by repeated injections and potential risk of infection.

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Therefore, an alternative drug delivery medium was devised which would equate parenteral administration in order to perform a first metabolism step. Such a promising alternative is potentially the administration of a drug nasally. However, as with other methods for noninvasive medication, the bioavailability of a drug following intranasal administration is largely unpredictable depending inter alia on the chemical nature of the drug.

Thus, progesterone and propanolol are known to be absorbed from the nasal cavity to provide blood levels practically equal to those of intravenous administration.

Other examples are known for intranasal compositions of pharmaceutical active agents with molecular weights up to about 1KD such as compositions containing aerosolized ergopeptide alkaloids dissolved in aqueous ethanol (Swiss Invention Patent No. 636,011), pharmaceutically active fatty acid amine salts (Canadian Patent No. 988,852) and catecholamine suspended in a polyoxyethylene emulsified fatty acid (or ester) (European Patent Application No. 160,501).

In the last decades several polypeptide drugs, mainly synthetic ones, have been developed. Generally, due to incomplete absorption and digestive instability in the alimentary canal, polypeptides have been administered parenterally. This is probably why special nasal release studies of polypeptides have been intensified.

* stayed during recent years. It has been found that while some smaller peptides (up to about 10 amino acid residues) can be absorbed reasonably well intranasally from simple aqueous formulations, generally the nasal bioavailability of the larger polypeptides becomes incomplete and variable and increasing. with increasing molecular weight (for a review see L. Illum: Archiv for Pharmacology Chemi 95 (1987), 127-135).

In order to eliminate the disadvantages found mainly in the longer delivery polypeptide-containing nasal release compositions, the further incorporation of a variety of bio-compatible absorption promoting agents or so-called enhancers has been envisioned.

In this regard reference is made to European Patent Publication No. 111,841, which describes the absorption enhancing effect of a bile acid and to US Patent No. 4,476,116, which uses chelating agents such as EDTA.

For an insulin dependent diabetic patient of course, nasal compositions adapted to release insulin are highly preferred over preparations currently available for parenteral administration with the condition that insulin is absorbed from the nasal cavity to provide reasonable efficacy and content. For such compositions a variety of absorption enhancing agents have been designed, especially surfactants.

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X • β

British Patent No. 1,527,605 discloses ionic and nonionic surfactants such as bile acid salts and polyoxyethylene higher alcohol ethers, while the use of a polyoxyethylene higher alcohol specific ether, namely polyoxyethylene-9 is described in: R. Salzman et al., New England J. of Med. 312, 1078-1684 (1985). In U.S. Patent 4,548,922 other boosters are described, for example salts of taurodihydrofusidic acid.

The chemical structure of enhancers known hitherto deviates considerably from known cell membrane constituents, including those of the nasal cavity, this may possibly explain their natural inclination to cause nasal irritation or even permanent damage to the nasal membrane, particularly during chronic administration. More similar enhancers with other physiological surfactants such as phospholipids may be considered on this basis. However, according to the data described in British Patent No. 1,527,605 (supra) phospholipids in a commonly available long chain lecithin mixture have no detectable enhancement effect on insulin-containing nasal formulations.

It has now surprisingly been found that medium length chain phosphatidylcholines and phosphatidylethanolamines substantially enhance the intranasal absorption of pharmaceutically active compounds in

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X special polypeptides, without causing damage or irritation to the nasal mucosa. Intranasal absorption is further enhanced in formulations wherein a fatty acid, for example a vegetable oil, is mixed with the phospholipid.

Summary of the Invention

According to the first aspect of the present invention it provides a preparation for intranasal administration consisting of a pharmaceutically active agent and an absorption enhancing system consisting of at least one phospholipid of formula I.

H-CH-OR '

CH-OR

I H-CH-OP (O) (OH) -OR 'in which,

R 1 and R 1, the same or different, each represent a hydrogen atom or an alkyl, alkenyl, alkylcarbonyl, alkenylcarbonyl, alkadienylcarbonyl, alkatrienylcarbonyl or alkatetraenylcarbonyl group having less than 14 carbon atoms, provided that R 'and R is not a hydrogen atom, and

R 'represents a hydrophilic group chosen from the groups

2- (trimethylammonium) r-ethyl, 2-aminoethyl, 2-carboxy-2-aminoethyl, 2,3-dihydroxypropyl and pentahydroxycyclohexyl, thus consisting of choline-derived phosphatidyl (lecithins), ethanolamine, glycerol, serine and inositic, respectively. Eventually, but preferably, the absorption enhancing system

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V also comprises a fatty oil in a mixture with the phospholipid (s).

According to the second aspect of the present invention there is provided a process for preparing the compositions for intranasal administration, which comprises dispersing at least one phospholipid of formula I, optionally but preferably mixed with a fatty oil in a solvent. liquid or solid together with the pharmaceutically active agent in solution or as a powder, the solvent of which may optionally incorporate pd, preservatives and osmotic pressure controlling agents.

Preferred aspects and their detailed description

A preferred subclass of compounds of formula I are compounds wherein R 'and R' each represent an alkylcarbonyl group. Yet another preferred class of compounds of formula I are compounds wherein R 'represents

2- (trimethylammonium) ethyl, such as compounds known as lecithins. Yet another preferred aspect of the compounds of formula I, wherein R 'and R' each represent an alkylcarbonyl group of about 4 carbon atoms, preferably no more than 12 carbon atoms. The most preferred subclass of the compounds of formula I are the compounds wherein R 'and R' each represent a nonylcarbonyl group.

The preferred preparation of the present invention is a mixture containing 2 phospholipids of formula I. One of these two phospholipids may conveniently be a compound wherein R 'and R are each octanoyl, decanoyl or lauroyl. 0 the other of these two phospholipids may conveniently be a compound in which one of the two substituents represented by R * and R is a hydrogen atom and the other of the two substituents represented by R 'and R is an octanoyl, decanoyl or dodecanoyl (lauroyl).

Preferred exemplary compounds of formula I are:

Dioctanoyl-L-X - phosphatidylcholine,

Dioctyl-OL-tK-phosphatidylcholine,

Didecanoyl-L-α-Phosphatidylcholine,

Didecyl-OL-Λ-phosphatidylcholine,

Decyl-OL-X-lysophatidylcholine,

Dilauroyl-L-4-phosphatidylcholine,

Lauroyl-L-X-lysophosphatidylcholine.

The compounds of formula I, some of which are known, may be prepared by known methods.

Fatty oil optionally incorporated into the absorption enhancing system of the present invention is preferably a vegetable oil, more preferably soybean oil, peanut oil, coconut oil, corn oil, olive oil, sunflower oil or mixtures thereof.

In another preferred aspect of the present invention the pharmaceutically active agent is a polypeptide. A group of preferred polypeptides are insulin and insulin derivatives, for example insulin modified by chemical or enzymatic methods or recombinant DNA technology.

<img file="PT86370B_D0002.tif" />

or mixtures of such insulins, proinsulin and glucagon. Other preferred polypeptides are parathyroid hormones, parathyroid antagonist hormone, calcitonin, vasopressin, renin, proactive, growth hormone, thyroid stimulating hormone, corticotropin, corticotropin releasing factor, follicle stimulating hormone, luteinizing hormone, Chorionic Gonadotropin, Arterial Peptides, Interferon, Tissue plasminogen activator, Gammaglobulins, Factor VII, Factor VIII, growth hormone release hormone, luteinizing hormone release hormone, somatostatin and cholecystokinin.

The preparation of the present invention may be liquid, for example adapted for administration in the form of an aerosol or a solid, for example an acceptable spray powder. Liquid preparations such as aqueous compositions will usually be included as adjuvants, for example a pH buffer system, preferably a phosphate buffer, citrate or acetate buffers, a preservative agent or an osmotic pressure controlling agent, for example. glycerol or sodium chloride for example. The powder compositions may contain a pharmaceutically active agent and an absorption enhancing system in admixture with acceptable nasal administration diluents or mixtures thereof, for example cellulose or derivatives thereof, for example cellulosic ethers or carboxymethylcellulose sodium, starch or partially degraded starch such as dextrins, a long chain fatty acid or a salt thereof, for example aluminum stearate or an organic polymer, for example a derivative of

<img file="PT86370B_D0003.tif" />

acrylic acid or inorganic vehicles such as talc or diatomaceous earth.

Additional addition of water-absorbing polymers, for example polyethylene glycol or polyvinyl pyrrolidone may be suitable for improving the adhesion of the powder composition to the nasal mucosa.

Preferred liquid preparations are those wherein the solvent is water. Such preparations may be prepared by dispersing the aqueous absorption enhancing system containing the pharmaceutically active agent and adjuvant agents, dispersion by any method commonly used for suspensions or emulsions, for example by ultrasonic treatment. . The correction of the aqueous phase to the neutral value (ie to a value of pd between about

6.5 to about 8) can be performed at any of the preparation steps. Preferably, microemulsions are prepared wherein the size of the dispersed particles or droplets is on the order of 1ONM thus facilitating their passage through the nasal mucosa.

These microemulsions may be sterile filtered. The phospholipid content of formula I and fatty oil in the preferred compositions of the present invention is from 0.01% to%% W / V and 0.01% to 50% W / V, respectively, in the preparation. Because proteases and peptidases are associated with the nasal mucosa (see, RE Stratford and VHL Lee: Int. Journ. Pharmaceutics 30 (1986), 73-82) may be suitable to incorporate biocompatible peptidase and protease inhibitors in the polypeptide-containing compositions.

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The concentration of the pharmaceutically active agent in the compositions of the present invention will, of course, depend upon the agent chosen, in particular, on its efficacy, compared to its bioavailability by nasal administration and other routes of administration, for example by parenteral injection and on the frequency. administration dose associated with the desired single dose of the composition.

Such pharmacological data may routinely be obtained by those skilled in the art from animal experiments, for example, in terms of index values, such as those evaluated for insulin preparations in the examples provided hereinafter.

Taking insulin as an example, its concentration in the compositions of the present invention may be from about 5 to 1000 international units (IU) per ml, preferably from 50 to 5uu international units per ml.

The insulin compositions of the present invention preferably contain bovine, porcine or human insulin.

An exemplary method for preparing the insulin compositions of the present invention wherein the solvent is water is dissolving insulin, for example crystallized zinc insulin, for example the high purity insulin described in British Patent No. 1,285 0.025 in water in the presence of an acid, for example a hydrochloric acid. An aqueous solution of a preservative, for example phenol or an alkyl phenol, such as cresol or methyl P-hydroxy benzoate is prepared separately, optionally also containing

<img file="PT86370B_D0004.tif" />

an agent which renders the solution isotonic, such as sodium chloride or glycerol. In addition, the preservative solution may contain a buffering agent such as sodium phosphate, sodium citrate, sodium acetate or tris (trishydroxymethylamino methane) and a protease inhibitor. The resulting preservative solution is then mixed with the acidic insulin solution followed by the addition of a base, for example a sodium hydroxide solution, for correcting the pH to near neutral. 0 The phospholipid of formula I optionally in admixture with the fatty oil may be added to the insulin solution in the form of a solution or emulsion which is prepared by dissolving or suspending the phospholipid of formula I in water and, if necessary. necessary, subjecting this suspension to ultra-light treatment.

-sounds before mixing with insulin solution.

Alternatively, the phospholipid solution or emulsion may, if appropriate, contain a buffering agent and a preservative. After mixing, the pH value of the insulin preparation can be corrected for neutrality. Finally, the resulting insulin solution is &lt;? wi volunE calculated by the addition of water.

The compositions of the present invention may be used in any dosage delivery device adapted for intranasal administration. The device may be constructed to achieve an accurate optimal meter and the compatibility of its building elements, such as the container, valve and actuator, with the nasal composition and may be based on a mechanical pump system, for example a dose mobilizer. or a pressurized aerosol system. 0 aerosol system requires

<img file="PT86370B_D0005.tif" />

an inert propellant with respect to the composition. Suitable propellants may be chosen from gases such as fluorocarbons, hydrocarbons, nitrogen and nitrogen dioxide or mixtures thereof.

Further details of the practice of the present invention are provided by the following examples, which, however, should not be construed as imposing any kind of limitation on the scope of the present invention.

Insulin starting material used in examples 1 to 12 contained about 20 to 10 µg of zinc per Mg of nitrogen.

soybean oil and peanut oil had different degrees of purity corresponding to those set forth in USP XXI and NF XVI, respectively.

Example I

772 mg of human insulin was dissolved in 40 ml of 0.1 M hydrochloric acid and 1.6 g of anhydrous glycerol was added thereafter. Then 80 ml of water was added. The pH was adjusted to 7.4 with a 0.2 M sodium hydroxide solution. 1 g of didecanoyl Ir X -phosphatidylcholine was dissolved in 2 ml of 96% ethanol and injected by one hypodermic syringe in 10 ml of distilled water. The resulting cloudy solution was sonicated with a high energy ultrasonic probe for 10 minutes resulting in a colloidal solution which was added to the stirred insulin solution and then 100 ml of distilled water was added. This preparation, containing 200 international units per ml insulin

13 / was packaged in an aerosol suitable for nasal administration and 100 ml was administered to the nasal cavity of male NZW rabbits. An identical preparation, but free from didecanoyl-1 H -phosphatidylcholine, was also tested in rabbits.

At fixed time intervals, blood samples were taken from the marginal ear vein and glucose concentration was determined by the hexokinase method.

The results were:

<td>Glucose</td><td>in the blood</td><td colspan="2">as a percentage of</td><td colspan="2">initial fee:</td>

<td>Minutes after the treatment</td><td> 0</td><td> 30</td><td>6u</td><td> 90</td><td> 120</td>

<td>Insulin without additive</td><td>10</td><td> 100</td><td> 103</td><td> 99</td><td>wow</td>

<td>Insulin with didecanonoyl L-phosphatidyl- hill</td><td> 100</td><td> 56</td><td> 65</td><td> 70</td><td> 81</td>

Example 2

10 mg of didecanoyl L-β-phosphatidylcholine was dissolved in 100 mg of soybean oil and the solution was added with 5 ml of 0.1 M sodium phosphate buffer, pH 7.4.

The mixture was emulsified by ultrasonic treatment;

<img file="PT86370B_D0006.tif" />

2 ml of the 40U units per ml insulin solution was added to an emulsion and the pH was corrected to 7.4 and then 10 ml of water was added.

Following nasal application of this composition to rabbits, blood glucose concentration was controlled for 12 minutes. The total area of ​​the curve where simple blood glucose values ​​are expressed as a percentage of the initial value was assessed by the triangle method. The index was then calculated according to the following formula:

I index = 0.053 x A / D where A is the area on the curve for the test preparation, D represents the dose of the test preparation and factor 0.053 is an empirically derived factor of a subcutaneous application of an insulin preparation that acted fasting.

This test conducted for nasal insulin emulsion had a 24% index.

A similar preparation but free of vegetable oil had an index of 12% to 15%.

Examples 3 to 12

The preparations of Examples 3 to 6, 8 and 12 were prepared analogously to that described in Example I while the preparations of Example 7 and 9 to 11 were prepared by the method of Example 2. The following abbreviations are used in the table:

<img file="PT86370B_D0007.tif" />

KJ: Phosphatidylcholine

DDPC: Didecanoyl Phosphatidylcholine

DDPC: Dilauryl Phosphatidylcholine

The percent contents are by weight by volume. All preparations contained 80 international units per ml of insulin.

<td>Example Κώ</td><td>Phospholipid</td><td>vegetable oil</td><td>index</td>

<td> 3 4 5</td><td>0.5% plain lauryl PC 0.5% smooth myristoyl PC 0.5% plain stearoyl PC</td><td>none</td><td> 10.9% 3.8% 0.8%</td>

<td> 6</td><td>u, 5% DDPC + u, 2% lauroyl smoothPC</td><td>none</td><td> 13.9%</td>

<td> 7</td><td>0.5% DDPC + 0.2% lauroyl smoothPC</td><td>peanut oil 2%</td><td> 21.9%</td>

<td> 8</td><td>0.5% didecil-υ-ΡΟ</td><td>none</td><td> 21.9%</td>

<td> 9</td><td>0.5% didecyl-υ-ΡΟ + 0.5% ddpc</td><td>peanut oil 1%</td><td> 28.7%</td>

<td> 10</td><td>0.5% DDPC 0.5% DDPC</td><td>peanut oil 1%</td><td> 18.9%</td>

<td> 11</td><td>0.5% DDPC 0.5% dimyristoyl PC</td><td>peanut oil 1%</td><td> 14.3%</td>

<td> 12</td><td>0.5% DDPC</td><td>none</td><td> 11%</td>

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<img file="PT86370B_D0008.tif" />

Data show the effect of enhancing higher absorption of phosphatidylcholines with alkyl or acyl groups in the medium length chain.

Example 13

100 mg of didecanoyl · A-phosphatidylcholine was dissolved in 100 mg of soybean oil and the solution was added to 5 ml of pH 7.4 0.01 M sodium phosphate buffer containing 160 mg of glycerol. After emulsification of the mixture by sonication 100 mg of glucagon was added to the emulsion, the pH was corrected to 7.4 and 10 ml of water was added.

Following nasal application of this composition to rabbits, glucose concentration was monitored in blood samples taken from the marginal ear vein by the hexokinase method.

The following blood glucose concentrations were obtained with the following time:

<td colspan="6">Minutes after</td>

<td>treatment</td><td> 0</td><td> 15</td><td> 30</td><td>6th</td><td> 120</td>

<td>Glucagon-free booster system</td><td> 106</td><td> 107</td><td> 115</td><td> 111</td><td> 107</td>

<td>Reinforcing system with glucagon</td><td> 100</td><td> 144</td><td> 178</td><td> 188</td><td> 163</td>

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