NO901161L - TRANSMUCOSAL RELEASE FORMS AND A PROCEDURE FOR PREPARING THEREOF. - Google Patents

Abstract

Systemic absorption after non-enteral transmucosal release of certain drugs, especially pharmacologically active polypeptides, is increased from formulations containing a monosaccharide or an oligosaccharide, preferably a cyclodextrin.

Description

The description of the present invention lies within the field of drug delivery by non-enteral, transmucosal administration routes. In particular, the present invention relates to new pharmaceutical preparations designed for oral mucosal, rectal or nasal administration and a method for producing such preparations.

BACKGROUND OF THE INVENTION

Although non-invasive drug administration, such as oral, oral mucosal or rectal administration of a drug is arguably the most common to the patient, parenteral drug delivery is normally considered the most effective. In particular, drugs that are inactivated in or poorly absorbed by the digestive tract and drugs that are subject to extensive first-pass hepatitis metabolism after oral administration are normally given parenterally.

There are obvious disadvantages in connection with parenteral drug administration, such as the need for sterile delivery devices, pain, irritation and possible tissue damage caused by repeated injections and a potential risk of infection. Therefore, alternative means of drug delivery have been sought which are equivalent to parenteral administration in the sense that first-pass hepatitis metabolism is avoided. Examples of such potentially promising alternatives are drug administration through the oral mucosal, rectal or nasal route. However, it is a general experience with these methods of non-invasive drug administration that the biological availability of the drugs is very unpredictable, is strongly dependent on such factors as the relevant choice of delivery route, the chemical nature of the drug and the choice of suitable absorption-promoting excipients or carriers.

Rectal administration of a number of drugs, e.g. as suppositories, have long persisted in medical practice. Administration by the rectal route allows the drug to enter the circulation directly without first passing the liver. This was shown for propranolol by A.G. de Boer et al. (J. Pharm. Pharmacol.

33 (1981), 50). Propranolol is also absorbed from the nasal cavity.

The blood level achieved is almost similar to that for intravenous administration, which is also the case with intranasal delivery of progesterone.

Other examples of intranasal formulations of pharmaceutically active agents with molecular weights up to approx. 1 kD is known, e.g. mixtures containing ergopeptide alkaloids dissolved in aqueous methanol given as aerosols (Swiss Patent No. 636,011), salts of pharmaceutically active amines with fatty acids (Canadian Patent No. 988,852) and catecholamine suspended in a fatty acid (or ester) emulsified with polyoxyethylene (European Patent Publication No. .0.160.501 A).

Over the past 10 years, a number of (mainly synthetic) polypeptide drugs have been developed. In general, polypeptides are given parenterally due to incomplete absorption from and digestive instability in the alimentary canal. This is probably the reason why especially studies of transmucosal and especially nasal delivery of polypeptides have increased in recent years. It has been found that although some smaller polypeptides (up to approx. 10 amino acid residues) can be absorbed reasonably well intranasally from simple, aqueous formulations, in general nasal bioavailability of larger polypeptides is both incomplete and variable, and thus increases with increasing molecular weight (for overview see L. Illum: Archiv for Pharmaci and Chemi 94 (1987), 127-135).

With a view to overcoming the disadvantages found in trans-mucosal and especially in nasal delivery formulations containing larger polypeptides, the further introduction of a number of bio-

compatibility absorption promoting agents have been developed, especially so-called enhancers for liquid formulations and powder carriers for solid formulations.

In this context, reference is made to European patent application no. 0111,841 A, which describes the absorption-enhancing effect of a bile acid and US patent no. 4,476,116, which uses gelling agents such as EDTA.

Transmucosal formulations adapted for insulin delivery would naturally be strongly preferred for insulin-dependent diabetic patients over the currently available preparations for parenteral administration, provided that the insulin is absorbed to a reasonably efficient and constant extent from the chosen compartment. A number of absorption enhancing agents, particularly surfactants, have been prescribed for such formulations.

A moderate absorption by oral mucosal delivery of insulin in the presence of sodium glycocholate has been observed in dogs (M. Ishida et al.: Chem.Pharm. Bulletin 29 (1981), 810-816). Similar results have been obtained by rectal administration, both in the presence of surfactants and non-surfactants (T.Nishitate et al.: Journ.Pharm. Sciences 69 (1980), 744-745).

Ionic as well as nonionic surfactant enhancers such as bile acid salts and higher polyoxyethylene alcohol ethers in nasal formulations are described in British Patent No. 1,527,605, while the use of a specific higher polyoxyethylene alcohol ether, namely polyoxyethylene-9-lauryl ether is described in: R .Salzman et al. , New England J. of Med. 312 (1985), 1078,1084. Other reinforcements, e.g. salts of taurodihydrofusidic acid, are described in US patent no. 4,548,922.

The chemical structure of these previously known enhancers differs significantly from those that are known constituents of cell membranes, including those in the nasal cavity. This feature could possibly explain their general tendency to cause nasal irritation or even persistent damage to the nasal membrane, especially with chronic administration. According to Danish patent application no. 3700/87, enhancers that are more closely related to mucosal membrane components, such as medium-length phospholipids, are significantly more effective and well tolerated. Similarly acceptable carriers for nasal powder formulations are such water-insoluble bases as cellulose, starch and their chemical derivatives, other polymers, or other macromolecular carriers as described by T. Nagai et al., e.g. in the US

Patent No. 4,613,500.

The present invention is based on the observation that certain water-soluble saccharides show a surprisingly high efficiency as absorption enhancement aids, and further appear to be well tolerated by chronic administration on mucosal surfaces.

SUMMARY OF THE INVENTION

Thus, according to a first aspect, the invention provides a preparation for transmucosal drug delivery, which preparation comprises a pharmaceutically active agent and an absorption-enhancing carrier comprising at least one saccharide or a metabolite thereof selected from the group consisting of a monosaccharide containing from 3 to 8 carbon atoms and an oligosaccharide containing from 6 to 16 monosaccharide, preferably glucosyl, residues.

According to another aspect of the present invention, a method is provided for preparing a preparation for transmucosal drug delivery, which method consists in dispersing the pharmaceutically active agent in a carrier, e.g. with mechanical devices or by freeze-drying an aqueous solution or suspension, which carrier comprises at least one saccharide as defined in claim 1 below, and possibly one or more additional ingredients, such as a powdery, waxy or liquid diluent, and pH buffering , preservative and osmotic pressure controlling agents.

PREFERRED EMBODIMENTS OF THE INVENTION AND DETAILED DESCRIPTION THEREOF

Preferred monosaccharides are selected from the group consisting of tetroses, pentoses, hexoses and heptoses. Particularly preferred are D-erythrose, D-ribose, D-ribulose, D-xylose, D-lyxose, L-arabinose, D-mannose, L-sorbose and D-sedoheptulose, all of which are found in nature. However, the corresponding enantiomeric monosaccharides are also considered to be within the scope of this invention. The most preferred monosaccharides are D-lyxose, D-xylose, D-ribose, D-mannose and L-sorbose. Examples of monosaccharide metabolites are monosaccharide phosphates, especially those phosphorylated on a terminal hydroxyl group.

A preferred group of oligosaccharides are cx-, β-, y-cyclodextrin, o-substituted derivatives thereof, preferably those substituted with acyl, carboxyalkyl or alkyl, especially with methyl, and similarly branched cyclodextrins where the branching consists of a carbohydrate residue, especially a maltosyl or glucosyl residue.

The most preferred oligosaccharides are α-, ε-, and γ-cyclodextrin and derivatives thereof which have one or more maltosyl branches. Branched cyclodextrins are previously known, e.g. from US patent no. 4,668,626.

Another preferred embodiment of this invention is the pharmaceutically active agent polypeptide. A group of preferred polypeptides are insulin and insulin derivatives, e.g. insulin that has been modified by chemical or enzymatic methods or by recombinant DNA technology, or mixtures of such insulins, proinsulin and glucagon. Other preferred polypeptides are parathyroid hormone, parathyroid hormone antagonist, calcitonin, vasopressin, renin, prolactin, growth hormone, thyroid-stimulating hormone, corticotropin, corticotropin-releasing factor, follicle-stimulating hormone, luteinizing hormone, chorionic gonadotropin, arterial peptides, interferon, tissue plasminogen activator, gamma globulins, Factor VII, Factor VIII, weight hormone-releasing hormone, luteinizing hormone-releasing hormone, somatostatin and cholecystokinins.

The preparation in this invention can be solid, e.g.

a suppository for rectal administration or a powder acceptable for snorting, or it may be liquid, e.g. a solution or suspension designed for administration as a spray.

Powder formulations for nasal use may contain the pharmaceutical active agent and the absorption enhancing carrier of that invention in admixture with nasally acceptable water-insoluble, powdery diluents or mixtures thereof, e.g. cellulose or derivatives thereof, e.g. cellulose ethers or sodium carboxymethyl cellulose, starch, a long-chain fatty acid or a salt thereof, e.g. aluminum or magnesium stearate, an organic polymer, e.g. of acrylic acid or a derivative or salt thereof or inorganic diluents such as talc or diatomaceous earth. It is recognized (compare US patent no. 4,613,500 above) that these and similar compounds can themselves act as carriers, e.g. for intranasal delivery. Within the scope of the present invention, which however relates to significantly more effective carriers, the term diluent is used for these previously known carriers.

In a preferred embodiment, the amount of diluent mixed with the water-soluble carrier is in the range from 0 to 80%, in particular from 0 to 50% by weight. In the most preferred embodiment of this invention, the water-soluble carrier is undiluted.

Powdery preparations can be prepared by dispersing the solid substance, e.g. crystalline, amorphous or freeze-dried pharmaceutical active agent in the powdered carrier, optionally mixed with a diluent, the dispersion being carried out with mechanical aids, e.g. a mortar or by painting. Alternatively, the pharmaceutical active agent can be dissolved or suspended in water together with the carrier, optionally mixed with the water-insoluble diluent, if necessary followed by adjustment of the pH to neutral conditions, i.e. to a pH in the range from approx. 6.5 to approx. 8. The suspension can then be brought to dryness, e.g. by freeze drying.

Because proteases and peptidases associate with the nasal mucosa (see R.E. Stratford and V.H.L.Lee: Int. Journ. Pharmaceutics 30 (1986), 73-82) it may be desirable to ingest biotolerable protease and peptidase inhibitors in polypeptide-containing formulations .

Liquid preparations where the diluent is water will normally contain additional agents, such as a pH buffering system, e.g. a phosphate, citrate or acetate buffer, a preservative and an agent that controls osmotic pressure, e.g. glycerol or sodium chloride.

Liquid preparations can also combine the concept for the present invention with the concept from Danish patent application no. 3700/87, above, regarding such absorption enhancers as medium-chain phosphatidylcholines and fatty oils. Such liquid preparations could contain the pharmaceutical active agent and the water-soluble saccharide dissolved and/or dispersed in a solution of phosphatidylcholine(s) in the fatty oil or in an emulsion thereof with an aqueous phase.

The concentration of the pharmaceutical active agent in the preparations of this invention will of course depend on the particular agent chosen, on its effectiveness, on a comparison of its bioavailability by transmucosal administration and by other routes of administration, e.g. parenteral injection, and of the desired frequency of administration combined with the desired single dosage of the formulation.

Such pharmacological data can be routinely obtained by one skilled in the art from animal experiments, e.g. through index values, such as those calculated for insulin preparations in the examples given hereafter.

Taking insulin as an example, its concentration in the preparation of this invention may range from approx. 5 to 10,000 international units (IU) per gram, preferably from 50 to 10,000 international units (IU) per gram, preferably from 50 to 5,000 IU per gram.

Taking glucagon as an example, its concentration in the preparation of this invention may be in the range of about 0.1 to 800 mg per gram, preferably from 1 to 600 mg per gram.

The insulin preparations in this invention preferably contain bovine, porcine or human insulin.

An example of a way to prepare the insulin preparations in this invention consists in dissolving insulin, e.g. crystalline zinc insulin, e.g. the highly purified grade of insulin described in British Patent No. 1,285,023 in water in the presence of an acid, e.g. hydrochloric acid. An aqueous solution of a preservative, e.g. phenol, an alkylphenol, such as cresol, or methyl p-hydroxybenzoate are prepared separately, optionally also containing an agent that makes the solution isotonic, such as sodium chloride or glycerol. Furthermore, the preserving solution may contain a buffering agent such as sodium phosphate, sodium citrate, sodium acetate or TRIS (tris-(hydroxymethyl)aminomethane) and a protease inhibitor. The resulting preservation solution is then mixed with the acidic insulin solution followed by the addition of a base, e.g. a sodium hydroxide solution, to adjust the pH to neutral. The saccharide carrier can be added to the insulin solution as an aqueous solution or suspension. Alternatively, the saccharide solution or suspension may, if desired, contain the buffering agent and the preservative. After mixing, the pH value in the insulin preparation can be readjusted to neutral. Finally, water is removed from the resulting mixture, e.g. by freeze-drying.

Powder formulations of this invention can be used in any dosage dispenser device designed for transmucosal administration. As an example, intranasal delivery can be achieved from a capsule containing the desired dose of the powder formulation. When inserted into a nasal insufflator equipped with an adapter, the capsule is pierced by a needle, which thereby produces a hole at each end. Adapters are then contacted with the nostril, and the capsule is emptied either by means of an air flow (e.g. from a mechanical pump device) or a propellant gas flow.

Liquid preparations may be used in any dosage-dispensing device designed for intranasal administration. The device should be designed with a view to ensuring optimal measurement accuracy and compatibility of its constructive elements such as container, valve and activator in the nasal formulation and could be based on a mechanical pump system, e.g. it in a metered-dose nebulizer, or on an aerosol system under pressure. The Aerosol system requires that the propellant must be inert to the formulation. Suitable propellants can be selected from such gases as fluorocarbons, hydrocarbons, nitrogen and nitrous oxide or mixtures thereof.

Further details for practicing this invention are given in the form of the following examples, which, however, should not be considered to place any kind of limitation on the scope of this invention.

The insulin starting material used in the examples contained approx. 20 to 30 jjg zinc per mg nitrogen.

The monosaccharides and α-, β- and γ-cyclodextrins are commercially available products. The branched maltosyl cyclodextrin was prepared by the method described in US Patent No. 4,668,626 above.

Example 1-12

The preparations in the following examples were prepared by mixing the indicated dose of human insulin with the selected saccharide or diluted saccharide (20 mg).

The preparations were tested in a rabbit model, where 4 to 8 rabbits were treated with the nasal insulin preparation (20 mg per animal). At 0, 15, 30, 60 and 120 minutes after treatment, blood samples were taken and the concentration of blood glucose was determined. Each of these blood glucose concentrations was expressed as a percentage of the initial glucose concentration, and with the triangle method the area between average blood glucose versus time curve and curve f(time) = 100 was calculated. An index comparing the hypoglycaemic effect of the nasal preparation with the effect of a standard subcutaneous injection of a rapid-acting insulin preparation is then calculated with the formula:

where A is the area above the curve for the test preparation, D is the dose of the test preparation in IU/animal, and the factor 0.053 is an empirically derived factor from a subcutaneous application of a fast-acting insulin preparation.

Example

Example 13

4.53 mg of human insulin was ground in a mortar with 395.47 mg of cx-cyclodextrin giving a preparation with an insulin content of

0.3 IU per mg.

When tested in the rabbit model in example 1-12, an index of 42 was found for this preparation.

Example 14

2.91 mg of human insulin was ground in a mortar with 717.09 mg of cx-cyclodextrin.

The ground powder was sprayed with a solution of 80 mg of didecanoylphosphatidylcholine in a suitable volume of dilute ethanol containing approx. 30 vol% water and then allowed to dry.

The dried powder was passed through a 0.7 mm mesh sieve and finally through a 0.2 mm mesh sieve which gave a preparation with an insulin content of 0.1 IU/mg.

When tested in the rabbit model in example 1-12, a

index of 8 8 found for this preparation.

Example 15

The procedure described in Example 14 was followed

with 9.06 mg of human insulin, 750.94 mg of ribose and 40 mg of didecanoylphosphatidylcholine which gave a preparation with an insulin content of 0.3 IU/mg.

When tested on the rabbit model from examples 1-12, an index of 2 2 was found for this preparation.

Example 16

The procedure described in Example 14 was followed

with 2.3 mg human insulin, 537.7 mg cx-cyclodextrin and 60 mg didecanoylphosphatidylcholine dissolved in ethanol containing approx. 4 volume% water which gave a preparation with an insulin content of 0.1IU/mg.

When tested in the rabbit model in examples 1-12, an index of 95 was found for this preparation.

Example 17

4 mg of human glucagon was ground in a mortar with 796 mg of α-cyclodextrin which gave a preparation with a glucagon content of 5 mg/g.

The preparation was tested in a rabbit model where 4 to 8 rabbits were treated with the nasal glucagon preparation (20 mg/animal). At 0, 15, 30, 60 and 120 minutes after treatment, a blood sample was taken, and the concentration of blood glucose was determined.

Each blood glucose concentration was expressed as a percentage of the initial glucose concentration, and by the triangle method the area between the curve t(time) = 100 and the average blood glucose versus time curve was calculated. This area divided by the administered dose is used as a measure of the hyperglycemic effect of the treatment.

In this experiment, the present preparation gave an area

per dose of 74,876.

Example 18

The procedure described in Example 14 was followed

with 4 mg human insulin, 716 mg a.cyclodextrin and 80 mg didecanoylphosphatidylcholine dissolved in ethanol containing approx. 4% by volume of water and gave a preparation with a glucagon content of 5mg/g.

When tested as described in example 17, this preparation gave an area per dose of 107,683.

Claims (13)

1. Preparation for non-enteral, transmucosal drug delivery, characterized in that it comprises a pharmaceutical active agent and an absorption-enhancing carrier comprising at least one saccharide or a metabolite thereof, which saccharide is selected from the group consisting of a monosaccharide containing from 3 to 8 carbon atoms and an oligosaccharide containing from 6 to 16 monosaccharide, preferably glycosyl, residues. 2. Preparation according to claim 1, characterized in that the monosaccharide is selected from the group consisting of a tetrose, a pentose, a hexose and a heptose. 3. Preparation according to claim 2, characterized in that the monosaccharide is D-erythrose, D-ribose, D-ribulose, D-xylose, D-lyxose, L-arabinose, D-mannose, L-sorbose or D-sedoheptulose. 4. Preparation according to claim 3, characterized in that the monosaccharide is D-lyxose, D-xylose, D-ribose, D-mannose or L-sorbose. 5. Preparation according to claim 1, characterized by the oligosaccharide is selected from the group consisting of cx-cyclodextrin, β-cyclodextrin, Y-cyclodextrin and a branched cyclodextrin. 6. Preparation according to claim 5, characterized by the oligosaccharide is a cx- or p <-> cyclodextrin. 7. Preparation according to claims 1 to 6, characterized in that the pharmaceutical active agent is a polypeptide. 8. Preparation according to claim 7, characterized in that the polypeptide is insulin, an insulin derivative, a mixture of insulin and at least one insulin derivative, or a mixture of insulin derivatives. 9. Preparation according to 8, characterized in that the insulin content is in the range from 5 to 10,000, preferably from 50 to 5,000 international units per grams of the preparation. 10. Preparation according to claim 7, characterized in that the polypeptide is glucagon. 11. Preparation according to claim 10, characterized in that the glucagon content is in the range from 0.1 to 800, preferably from 1 to 600 milligrams per grams of the preparation. 12. Method for preparing a preparation for non-enteral, transmucosal drug delivery, which method comprises dispersing a pharmaceutical active agent in a carrier comprising at least one saccharide as defined in claims 1 to 6, and optionally one or more auxiliary ingredients selected from the group consisting of of a powdery, waxy or liquid diluent, a pH buffering agent, a preservative and an osmotic pressure controlling agent. 13. Any new feature or combination of features as described herein.