Method of pharmaceutical agent production for intranasal feed

The invention relates to pharmaceutical compositions for intranasal administration.

Non-invasive drug delivery, such as oral or rectal administration, is undoubtedly most convenient for the patient, but is usually considered to be the most effective parenterally. In particular, substances that are inactivated or poorly absorbed in the stomach and intestinal system, or substances that are largely degraded on first pass through the liver, are usually administered parenterally.

However, parenteral administration is associated with obvious disadvantages such as the need for sterile instruments, pain and irritation upon repeated injections and the potential risk of infection. For this reason, other routes of administration are sought for these agents, which would be equivalent to parenteral administration in the sense that there would be a first pass through the liver much later. One of these promising routes is nasal administration. However, as in other instances of non-invasive administration, the bioavailability of substances following nasal mucosal administration cannot be predicted, since this availability largely depends on the chemical nature of the substance administered.

For example, it is known that progesterone and propranolol are absorbed from the nasal cavity so that blood levels that are nearly equal to the concentration following intravenous administration can be assured. Another example of administration into the nasal cavity is pharmaceutically active agents with a molecular weight of up to about 1 kD. for example, compositions containing ergopeptide alcoloids dissolved in a mixture of water and ethanol and administered as aerosols have been described in Swiss Patent No. 5,960,549. 636 These may be, for example, salts of pharmaceutically active amines with aliphatic acids as described, for example, in Canadian Patent No. 988,852 and catecholamines which are suspended in aliphatic acids or esters emulsified with polyoxyethylene as described. European Patent Application Publication No. 160,501.

Over the past decades, a number of predominantly synthetic drugs of the polypeptide type have been developed. Usually, polypeptides need to be administered parenterally due to incomplete absorption from the gastrointestinal tract and due to their instability in the tract. This is probably the cause that led to a number of studies on the possibility of administering these substances through the nasal mucosa. It has been found that some small polypeptides of up to ten amino acid residues are readily absorbed by the nasal mucosa from simple aqueous solutions, while the bioavailability of larger polypeptides is incomplete and changeable, with these disadvantages escalating with increasing molecular weight, as summarized for example in L Illum, Archive for Pharmacies of Chemi 94 (1987, 127-135).

In order to overcome the disadvantages associated, in particular, with the absorption of compositions comprising larger polypeptides through the nasal mucosa, it has been proposed to incorporate various substances which promote absorption and are physiologically acceptable in the aforementioned compositions.

For example, published European Patent Application No. 111,841 proposes the use of bile acids to facilitate absorption, and US Patent No. 4,476,116 uses chelating agents such as EOTA for the same purpose.

Intranasal formulations adapted for insulin administration would be highly advantageous in insulin dependent patients for whom only parenteral administration remains at present, provided that insulin is absorbed from the nasal cavity in an effective and sustained manner. Meanwhile, a variety of absorption enhancers, especially wetting agents, have been proposed for these compositions.

Both ionic and nonionic surfactants for this use, for example, bile salts and ethers of polyoxyethylene and higher alcohols, have been described in British Pat.

527 605, the use of specific substances of this type, for example 9-polyoxyethylene lauryl ether, has been described by R. Salzman et al., New England J. of Med. 312 (1985), 1078-1084.

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Other substances for the same use, for example salts of taurodihydrofusidic acid, have been described in U.S. Pat. No. 4,548,922.

The chemical structure of the substances known to date for this use differs substantially from the known components of the cell membrane, including the cell membranes in the sinus cavity. This property probably explains their general glass to induce irritation of the nasal mucosa or even to induce permanent damage to the nasal mucosa, especially when sustained administration is required.

For this reason, it would be desirable to develop other substances of a similar type that are closer to physiologically wetting agents, such as phospholipids. However, British Patent Specification No. 1,527,605 discloses that phospholipids in a commercially available blend of lecithin with other chains had no demonstrable effect on the absorption of insulin formulations.

•• rf. It has now been unexpectedly found that phosphatidylcholines and mid-chain phosphatidylethanolamines substantially improve the absorption of pharmaceutically active compounds, particularly polypeptides, through the nasal mucosa without damaging or irritating the mucosa. Absorption through the nasal mucosa can be further improved by mixing with said phospholipid an oil containing aliphatic acids, for example vegetable oil.

Accordingly, the present invention provides a composition for intranasal administration comprising a pharmaceutically active agent and at least one phospholipid of formula I

H - CH - OH '

CH-OR (i)

H - CH - O - P (O) (OH) -, OR'D where

R 'and R' are the same or different hydrogen, alkyl, alkenyl, alkylcarbonyl, alkenylcarbonyl, alkadienylcarbonyl, alkatrienylcarbonyl or alkatetraenylcarbonyl in each case up to 14 carbon atoms, provided that both substituents are not both hydrogen and

R is a hydrophilic group of 2- (trimethylammonium) ethyl, 2-aminoethyl,

2-carboxy, 2-aminoethyl, 2,3-dihydroxypropyl and pentahydroxycyclohexyl, as an absorption promoting system and diluent, optionally containing a pH adjusting buffer, a preservative and an osmotic pressure adjusting agent.

They are therefore phosphatidyl derivatives of choline (lecithins), ethanolamine, glycerol, lilac and inositols. Optionally, but preferably, the system also comprises an oil containing aliphatic acids in admixture with said phospholipid or phospholipids.

Compositions for intranasal administration of the aforementioned type may be obtained by dispersing at least one phospholipid of the formula I, optionally but preferably in admixture with an oil containing aliphatic acids in a solid or liquid diluent, together with a pharmaceutically active substance in solution or powder, said diluent optionally further comprising a buffer, a preservative or an osmotic pressure adjusting agent.

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A preferred group of compounds of formula I are those wherein R 1 and R 2 are both alkylcarbonyl. Another preferred subgroup of compounds of formula I are those wherein R is 2- (trimethylammonium) ethyl, for example lecithin. Another suitable group of compounds of formula I are those in which R and R are alkylcarbonyl groups of about 4 carbon atoms up to 12 carbon atoms. The most preferred subgroup of compounds of formula I are those wherein both R and R are nonylcarbonyl.

A suitable composition is one comprising two phospholipids of formula I. One of the two phospholipids may be a compound in which R * and R are simultaneously octanoyl, decanoyl or lauroyl. The other of the two phospholipids may be a compound in which one of R 1 and R 2 is hydrogen and the other is octanoyl, decanoyl or dodecanoyl (lauroyl).

Examples of preferred compounds of formula (I) are the following: lactanoyl L-O-phostatidylcholine, di-alkyl-N-β-phosphatidylcholine, didecanoyl L-N-phosphatidylcholine, didecyl-OL-ob-phosphatidylcholine, decyl-OL-ys-lysofadiduryl choline, L-o-6-phosphatidylcholine, lauroyl L-o-6 -lysophosphatidylcholine.

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Compounds of formula I, some of which are known, can be prepared by known methods.

Oils containing aliphatic acids which may optionally be incorporated into the compositions according to the invention are preferably vegetable oils, in particular soybean oil, peanut oil, coconut oil, corn oil, olive oil, sunflower oil or mixtures thereof.

In another preferred embodiment of the invention, the polypeptide is a pharmaceutically active agent. One preferred group of polypeptides is insulin and its derivatives, for example insulin, modified by chemical or enzymatic techniques or technology using recombinant DNA, or a mixture of these insulin derivatives, proinsulin and glucacone. Another preferred group of polypeptides for use herein is the parathyroid hormone, hormone antagonist, calcitonin, vasopressin, renin, prolactin, growth hormone, TSH, corticotropin, corticotropin releasing factor, follicle-stimulating hormone, luteinizing hormone, interferon, chorionic gonadotropic, tissue plasminogen activator, gammaglobulins, factor VII, factor VIII, growth hormone releasing hormone, hormone, releasing luteinizing hormone somatostatin and cholecystokinins.

The composition according to the invention may be a liquid, for example intended for administration in the form of a spray or a solid, for example a snuff powder. Liquid formulations which are of the aqueous type will usually contain excipients, for example pH adjusting buffers, preferably phosphate, citrate or acetate buffers, preservatives and osmotic pressure regulators, for example glycerol or sodium chloride. Powder formulations may contain a pharmaceutically active agent and a system that facilitates absorption with a powdered diluent such as cellulose or cellulose derivatives such as cellulose ether or sodium carboxymethylcellulose, starch or partially decomposed starch such as dextrins, longer chain aliphatic acids or salts thereof , for example magnesium stearate, an organic polymer such as acrylic acid derivatives or inorganic excipients, such as talc or diatomaceous earth. Furthermore, water-absorbing polymers, such as polyethylene glycol or polyvinylpyrrolidone, may be added to improve the adherence of the powdered composition to the nasal mucosa.

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Preferred liquid compositions contain water as a diluent. The liquid compositions may be prepared by dispersing the absorption aid system in an aqueous medium containing the pharmaceutically active ingredient and excipients, and dispersing by any conventional means for producing a suspension or emulsion, for example by sonication. Adjustment of the aqueous phase to neutral pH, i.e., between 6.5 and B, is accomplished by any conventional system. Preferably, microemulsions are prepared in which the size of the dispersed particles or droplets is of the order of 10 nm, thereby facilitating their passage through the nasal mucosa. These microemulsions can be sterilized by filtration. The content of phospholipids of the formula I or an oil containing aliphatic acids in the preferred compositions obtained by the process of the invention is in the range of 0.01 to 10 g per 100 ml to 0.01 to 50 g / 100 ml. Due to the fact that proteases and peptidases are loaded in the nasal mucosa as described by R. E, Stratford and V HL Lee: Int. J. Pharmaceutics 30 (1986), 73-82, it may be desirable to incorporate biologically acceptable protease and peptidase inhibitors into polypeptide compositions.

The concentration of the pharmaceutically active agent in the compositions obtained by the method of the invention will, of course, depend upon the selected agent, its efficacy, its bioavailability ratio through the nasal mucosa and by other means, for example parenteral administration and the desired frequency of administration in combination with the desired. a single dose of the composition. These pharmacological data can be readily obtained by animal experimentation, for example in the form of an index, as these assays are performed for insulin and will be exemplified.

In the case of insulin, its concentration in the composition according to the invention may be in the range of 5 to 1000 international units per ml, preferably 50 to 500 units per ml.

The insulin-containing compositions preferably comprise bovine, swine or human insulin.

In the case of insulin preparations, the diluent may be water and may be carried out by dissolving insulin, for example, crystalline zincinsulin, for example, high purity insulin, disclosed in British Patent Specification No. 1,285,023 in water in the presence of an acid, for example hydrochloric acid. Separately, an aqueous solution of a preservative such as phenol, an alkyl phenol such as cresol or methyl p-hydroxybenzoate is prepared, optionally also containing a solution isotonicity agent such as sodium chloride or glycerol. In addition, the solution may contain a preservative and a buffer such as sodium phosphate, sodium citrate, sodium acetate or tris [tris (hydroxymethyl) aminomethane] and a protease inhibitor. The resulting preservative-containing solution is then mixed with an acidic insulin solution and a base such as sodium hydroxide solution is added to adjust the pH to the neutral range. The phospholipid of the formula I, optionally in admixture with an oil containing aliphatic acids, is added to the insulin solution in the form of a solution or an emulsion which is prepared by dissolving or suspending the phospholipid of the formula I in water and optionally sonicating the resulting suspension. before mixing with the insulin solution. Alternatively, a buffer and a preservative may be incorporated into the phospholipid solution or emulsion. After mixing, the pH of the resulting insulin composition can be readjusted to neutral. Finally, the resulting insulin solution is made up to the calculated volume by adding water.

The composition of the present invention can be used in any device that provides dosing and is adapted for administration to the nasal cavity. This device should ensure optimal dosing accuracy and should not break down the nasal mucosa formulation, such as a mechanical pump such as a nebulizer or an aerosol that is pressurized. The aerosol system requires a propellant that is inert to the other components of the composition. Suitable propellants may be, for example, fluorinated hydrocarbons, hydrocarbons, nitrogen, nitrous oxide or mixtures of the foregoing.

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Further details relating to the practice of the invention will be illustrated by the following examples, which are not intended to limit the method of the invention.

The starting insulin used in Examples 1 to 12 contained approximately 20 to 30 µg zinc per ml nitrogen.

Purified soy and peanut oil corresponding to USP XXI and NF were used in the compositions. VXI.

Example 1

772 mg of human insulin is dissolved in 40 ml of 0.02 M hydrochloric acid and 1.6 g of anhydrous glycerol is added. The mixture is then made up to 00 ml with distilled water. The pH is then adjusted to 7.4 by the addition of 0.2 M sodium hydroxide, 1.0 g of didecanoyl 1-sO-phosphatidylcholine is dissolved in 2 ml of 96% ethanol and sprayed into 10 ml of distilled water by syringe for subcutaneous administration. The resulting turbid solution is sonicated for 10 minutes and the resulting colloidal solution is added to the insulin solution with stirring and the mixture is made up to 100 ml with distilled water. This composition, containing 200 units of insulin per ml, is placed in a nasal cavity sprayer and 100 µl of solution is administered to the nasal cavity of NZW rabbit males. In a similar manner, the same formulation was tested without didecanoyl L-4, -phosphatidylcholine.

Blood samples were taken from the peripheral vein of the ear of the rabbit at specified intervals and glucose concentration was determined by a hexocyanase assay. The results are shown in the following table.

Blood glucose in% of initial value

<td>Minutes after administration</td><td> 0</td><td> 30</td><td> 60</td><td> 90</td><td> 120</td>

<td>insulin without additives</td><td> 100</td><td> 100</td><td> 103</td><td> 99</td><td> 100</td>

<td>insulin with didecanoyl With L-β-phosphatidylcholine</td><td> 100</td><td> 56</td><td> 65</td><td> 70</td><td> 81</td>

Example 2

AND

100 ALIGN! mg of didecanoyl L-O-phosphatidylcholine was dissolved in 100 ml soybean oil and added to 5 ml 0.01 M sodium phosphate buffer at pH 7.4.

The mixture is then emulsified by sonication, 2 ml of an insulin solution containing 400 units of insulin per ml are added to the emulsion, the pH is adjusted to 7.4 and the mixture is made up to 10 ml with water.

After administration of the composition to the nose in rabbits, the blood glucose concentration is monitored for 120 minutes. The area above the curve in which the individual values ​​are expressed as a percentage of the initial value is determined by the triangle method, then the index is calculated according to the following formula:

index = 0.053 x A / D where

A means the area above the curve for the device under investigation,

D is the dose of the agent under investigation; and

0.053 is a factor derived empirically from the subcutaneous administration of fast-acting insulin formulations.

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Based on these calculations, the index for insulin emulsion for administration to the nasal cavity was determined to be 24%.

A similar composition, which was prepared without the addition of vegetable oil, had a corresponding index of 12-15%.

Examples 3 to 12

The compositions of Examples 3 to 6.8 and 12 were prepared in a manner similar to that of Example 1, while the compositions of Examples 7 and 9 to 11 were prepared according to the method of Example 2. The following abbreviations are used in the following table:

phosphatidylcholine PC didekanoylphosphatidylcholine DDPC dilaurylphosphatidylchOlin DLPC

The contents of the individual substances were 80 units of insulin / ml and are given in grams per 100 ml. All resources include

<td>example no.</td><td>phospholipid</td><td>vegetable oil</td><td>index</td>

<td> 3</td><td>0,5¾ lauroyl lysoPC</td><td> -</td><td> 10,9 ¾</td>

<td> 4</td><td>0.5¾ myristoyl lysoPC</td><td> -</td><td> 3,8 %</td>

<td> 5</td><td>0,5¾ stearoyl lysoPC</td><td> -</td><td> 0,8 %</td>

<td> 6</td><td>0.5¾ DOPC + 0.2¾ lauroyl lysoPC</td><td> -</td><td> 13,9 ¾</td>

<td> 7</td><td>0.5¾ DDPC + 0.2¾ lauroyl lysoPC</td><td>peanut oil 2¾</td><td>21,9 '-ό</td>

<td> 8</td><td>0.5¾ didecyl-0-PC</td><td> -</td><td> 21,9 ¾</td>

<td> 9</td><td>0.5¾ didecyl-O-PC + 0.5¾ DDPC</td><td>peanut oil 1¾</td><td> 28,7 %</td>

<td> 10</td><td>0.5¾ DDPC + 0.5 DLPC</td><td>peanut oil 1¾</td><td> 18,9 ¾</td>

<td> 11</td><td>0.5¾ DDPC + 0.5¾ dimyristoyl PC</td><td>peanut oil 1¾</td><td> 14,3 %</td>

<td> 12</td><td>0,5¾ DDPC</td><td> -</td><td> 11,0 %</td>

The data show that the use of phosphatidylcholine with medium chain acyl or alkyl groups has a very good effect on insulin absorption.

Example 13

100 ALIGN! mg of didecanoyl L -? - phosphatidylcholine was dissolved in 100 mg of soybean oil and added to 5 ml of 0.01 M sodium phosphate buffer pH 7.4 containing 160 mg of glycerol. After ultrasonication of the mixture, 100 mg of glucagon is added to the emulsion, the pH is adjusted to 7.4 and water is added to 10 ml. ·

Following administration to rabbits in the nose, the blood glucose concentration from the peripheral ear vein was determined by the hexokinase method.

The results are shown in the following table, which shows the blood glucose concentration versus time.

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<td>Minutes after administration</td><td> 0</td><td> 15</td><td> 30</td><td> 60</td><td> 120</td>

<td>glucagon without auxiliary system</td><td> 100</td><td> 107</td><td> 113</td><td> 111</td><td> 107</td>

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

Example 14

When an intranasal formulation containing 50 mg of an atrial secretion peptide of 15 amino acids dissolved in physiological saline was administered, anesthetized rabbits were able to obtain urine levels of 0.0375 ml / min. By administering 25 µg of the same peptide in sodium chloride solution at the same concentration with 0.1% lauroyllysophosphatidylcholine also intravasally, the amount of urine produced was 0.575 ml / min.