MXPA97004551A - Formulations in powder containing melecitose as a diluye - Google Patents

Abstract

A powder formulation is provided for the administration of medically useful polypeptides, comprising a medically useful polypeptide with melezitose as they dilute

Description

DUST FOUNDATIONS OCTE C! ONTIENEN MFT.ECTTO.q? POMO T7N DILUYENTE CftMPO OF THE INVENTION The present invention relates to powdered formulations containing medically useful polypeptides.

ANT TECHNICAL PERSONNEL Polypeptide powders containing medically useful polypeptides and pharmaceutically acceptable carriers or diluents can be prepared by administration by inhalation or in some other way. Powder preparations of inhalable polypeptides have been described in O95 / 00127 and O95 / 00128. Diluents are commonplace in pharmaceutical preparations, especially in formulations for inhalation. They are used to stabilize various drugs during storage manufacture and to adjust the amount of powder that constitutes unit doses - in general, powder inhalers are capable of delivering a drug substance with good dose precision only for certain dose sizes, REF: 24881 while different medications which have variable potencies must therefore be supplied in different amounts. Since these amounts are often too small to ensure adequate dose accuracy, diluents are added to provide the desired dose size. Previously, reducing sugars such as lactose and glucose have been used as diluents in powder polypeptide formulations. However, these have the tendency to react with the polypeptides and therefore are not satisfactory. It is suggested in WO95 / 00127 and WO95 / 00128 in relation to polypeptide powders for inhalation, that non-reducing sugars such as raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch can be preferred for polypeptide powders. It has been found that melecitosa is an exceptionally good diluent compared to other possible non-reducing sugars for polypeptide powder formulations, which provides an unexpectedly high fraction of respirable dust when inhaled.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a powdered formulation for the administration of medically useful polypeptides, comprising a medically useful polypeptide with melezitose as a diluent. The administration is preferably by inhalation. The melecitosa can constitute, for example, D-melecitosa (α-D-melecitosa), β-D-glucopyranoside, O-α-D-glucopyranosyl-1,3-β-D-fructofuranosyl (β-D-melecitosa) or isomelecitosa. The melecitosa may be, for example, in the form of monohydrate or dihydrate. The powder formulation of the present invention has been found to be very effective for oral inhalation, which provides a higher fraction of respirable particles compared to powder formulations with other diluents, as described herein. As a result, a larger fraction of the inhaled powder will reach the lungs and a higher fraction of the polypeptide will be used. The powder formulation of the present invention is also suitable for use in nasal inhalation. The powder formulation of the present invention is suitable for systemic and local treatment. When local action in the respiratory tract is desired, other ingredients in the powder formulation are not necessary. When the systemic action is required, an enhancer, i.e., a substance which improves the absorption of the polypeptide in the respiratory tract, generally must be included in the formulation. Such substances are included in WO95 / 00127 and WO95 / 00128, incorporated herein by reference. In certain cases, small polypeptides are absorbed in the respiratory tract without the aid of an enhancer. In these cases, the enhancer of the melecitosa and medically useful polypeptide formulations can be excluded. Therefore, in different embodiments, the present invention provides a powder comprising a medically useful and melecitous polypeptide; a powder comprising a medically useful and melecitous polypeptide, and specifically including an enhancer; and a powder comprising a medically useful and melecitous polypeptide, specifically excluding an enhancer. The powder according to the present invention that excludes an enhancer is most useful when: (a) the local action of the polypeptide is desired; or (b) when the systemic action of smaller polypeptides is desired which are absorbed in the respiratory tract without the aid of an enhancer. The polypeptides which are absorbed in the respiratory tract without the aid of an enhancer can be identified using conventional cellular models, or preferably animal models, in the latter case, by comparing the plasma concentrations of the polypeptide after administration, for example, by means of the right powder feeding apparatus, or powders with and without improver. The powder that specifically includes an enhancer according to the present invention is most useful when the systemic action of polypeptides is desired which are not absorbed in the respiratory tract without the aid of an enhancer. Preferred mejsors include C8_16 fatty acids and salts thereof, bile salts, phospholipids and alkyl saccharides. Of the fatty acids and salts thereof, the salts of acid grades of C8.C16 are preferred. Examples of preferred fatty acid salts are sodium, potassium and lysine salts of caprylate (C8), caprate (C10), laurate (C12) and myristate (C14). Since the nature of the counterion is not of special importance, any of the salts of the fatty acids are potentially useful. A particularly preferred fatty acid salt is sodium caprate. Suitable bile salts may be, for example, salts of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycohenodeoxycholic acid, taurokenedeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid and ursodeoxycholic acid. Of the bile salts, trihydroxy bile salts are preferred. Further preferred are the salts of cholic, glycolic and taurocholic acids, especially the sodium and potassium salts thereof. The most preferred bile salt is sodium taurocholate. Suitable phospholipids can be, for example, single-chain phospholipids, for example, lysophosphatidylcholines, lysophosphatidylglycerols, lyso-phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylserines or double-chain phospholipids, for example, diacylphosphatidylcholines, diacylphosphatidyl-glycerols, diacylphosphatidylethanolamines, diacylphosphatidylinositols and diacylphosphatidylserines. Of the phospholipids, diacylphosphatidyl glycerols and diacylphosphatidylcholine are preferred, for example, dioctanoylphosphatidylglycerol and dioctanoylphosphatidylcholine. Suitable alkyl saccharides can be, for example, alkyl glucosides or alkyl maltosides such as decyl glucoside or dodecyl maltoside. The most preferred enhancers are bile salts.

The polypeptide may be any medical or diagnostically useful peptide or protein of small or medium size, ie, up to about 40 kD molecular weight (MW). Polypeptides having a molecular weight of up to 30 kD are expected to be most useful in the present invention, such as polypeptides having a molecular weight of up to 25 kD or up to 20 kD, and especially up to 15 kD, up to 10 kD or up to 5 kD. Preferably, the polypeptide is a peptide hormone such as insulin, glucagon, insulin C-peptide, vasopressin, desmopressin, cirticotropin (ACTH), corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), agonists and antagonists of gonadotropin-releasing hormone, gonadotrophin (gluteinizing hormone or LHRH), calcitonin, parathyroid hormone (PTH), bioactive PTH fragments such as PTH (34) and PTH (38), growth hormone (GH) (for example human growth hormone (hGH)), growth hormone releasing hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), Trigotropin releasing hormone (TRH), deoxyribonuclease (DNase), prolactin and follicle stimulating hormone (FSH) and analogs of any of the above. Other possible polypeptides include growth factors, interleukins, polypeptide vaccines, enzymes, endorphins, glycoproteins, lipoproteins and polypeptides involved in the blood coagulation cascade. The preferred polypeptide is insulin. In the powder formulation of the present invention, the melezitose can be present in an amount of up to about 100% by weight of the total powder. For example, the melecitosa can be present in an amount between 20% and almost 100%, for example between 30% and almost 100%, or between 40% and almost 100%, or between 50% and almost 100%, for example, between 60% and almost 100%, or between 65% and almost 100%, for example between 65% and 99%, or between approximately 70% and approximately 99%, for example between 80% and 98% in 'weight of the total weight of the dust. As with the pharmaceutical preparations, certain additives may also be included in the formulation, for example, for pH regulation, for example organic or inorganic salts, for flavoring or for increasing stability, for example condoms or preservatives, carbohydrates, amino acids, peptides and proteins. When the powder preparation of the present invention is designed for oral inhalation, the polypeptide can consist of (a) primary particles having a diameter of less than about 10 microns, for example between 0.01 and 10 microns, and preferably between 0.1 and 6 microns, for example between 0.01 and 5 microns, or (b) agglomerates of such particles. Preferably, at least 50% of the polypeptide consists of particles within the desired size range. For example, at least 60%, preferably at least 70%, more preferably at least 80% and more preferably at least 90% of the polypeptide consists of particles within the desired size range, when oral inhalation is desired. The melecitosa in the oral inhalation formulation may consist mainly of particles having a diameter of less than about 10 microns so that the resulting powder as a whole consists of optionally agglomerated primary particles having a diameter of less than about 10 microns; alternatively, the melecitosa can consist mainly of much larger particles ("coarse particles"), so that an "ordered mixture" can be formed between the active compounds and the melecitosa. In the ordered mixture, alternatively known as an interactive or adhesive mixture, the polypeptide particles can be distributed very uniformly on the surface of the coarse melecitosa. Preferably, in this case the active compounds are not in the form of agglomerates before the formation of the ordered mixture. The coarse particles can have a diameter of more than 20 micrometers, for example greater than 60 micrometers. Above the lower limits, the diameter of the coarse particles is not of critical importance, so that coarse particles of various sizes can be used, if desired, in accordance with the practical requirements of the particular formulation. There is no requirement for the coarse particles in the ordered mixture to be of the same size, but the coarse particles can advantageously be of similar size within the ordered mixture. Preferably, the coarse particles have a diameter of 60-800 micrometers. The least important particle size in nasal inhalation although small particles are desirable. An ordered mixture will not normally be used in nasal inhalation. A useful mechanism for supplying the powder in the respiratory tract of a patient is through a portable inhaler device suitable for inhaling dry powder. Many such devices, typically designed to deliver anti-asthmatic or anti-inflammatory agents in the respiratory system, are on the market. The powder preparation described can be manufactured in various ways, using conventional techniques. The particles in a range of required size can be obtained by any known method, for example by lyophilization or by controlled crystallization methods, for example crystallization using supercritical fluids; or by micronization methods. For example, polypeptide and melecitosa powders (and an optional improver) can be mixed dry, and then micronised the substances together; alternatively, the substances can be micronized separately, and then mixed. When the compounds to be mixed have different physical properties such as hardness and brittleness, the resistance to micronization varies and may require different pressures to decompose the substances to suitable particle sizes. Therefore, when micronized together, the particle size obtained from one of the components may not be satisfactory. In such a case it would be advantageous to micronise the different components separately and then mix them. It is also possible, when an ordered mixture is not desired, to first dissolve the components in a suitable solvent, for example water, to obtain mixing at the molecular level. This procedure also makes it possible to adjust the pH value to the desired level. To obtain a powder, the solvent must be removed by a process which retains the biological activity of the polypeptide. Suitable drying methods include vacuum concentration, open drying, spray drying and lyophilization. In general, temperatures greater than 40 ° C should be avoided for more than a few minutes, since some degradation of the polypeptide may occur. After the drying step, the solid material, if necessary, can be ground to obtain a coarse powder and then, if necessary, micronised. If desired, the powder can be processed to improve the flow properties, for example, by dry granulation to form spherical agglomerates with superior handling characteristics, before being incorporated into the proposed inhaler device. In such a case, the device must be configured to ensure that the agglomerates deagglomerate substantially before leaving the device, so that the particles that enter the respiratory tract of the patient are, by far, within the desired size range. When an ordered mixture is desired, the active compound can be processed, for example, by micronization in order to obtain, if desired, particles within the particular size range. The melecitosa can also be processed, for example, to obtain a desired size and desired surface properties, such as a particular surface to weight ratio, or certain roughness to ensure optimum adhesion forces in the ordered mixture. Such physical requirements of an ordered mixture are well known, as the various means for obtaining the ordered mixture which satisfies the requirements and can be easily determined by a person skilled in the art according to the particular circumstances. The powders of the present invention are useful for the local or systemic treatment of diseases and can be administered, for example, via the upper and lower respiratory tract, which includes the nasal route. As such, the present invention also provides a powder for use in therapy; the use of dust in the manufacture of a medicament for the treatment of diseases via the respiratory tract; and a method for treating a patient in need of therapy, which comprises administering to the patient a therapeutically effective amount of the powder of the present invention. The diseases which can be loaded with the powder of the present invention are any of which can be treated with the particular polypeptide in each case; for example, powders containing insulin according to the present invention may be used, for example, in the treatment of diabetes; powders containing corticotropin can be used, for example, in the treatment of inflammatory diseases; powders containing GnRH may be useful, for example, in the treatment of male infertility. The indications of all the mentioned types of polypeptides are well known. The powders of the present invention can also be used in the prophylactic treatment. Although the powders of the present invention are particularly directed to polypeptide powders for inhalation from powder inhaler devices, polypeptide powders can also be included in compositions for other forms of administration, for example, in solutions for injection and formulations in aerosol . The respirable fraction by oral inhalation of the powders of the present invention can be determined by the method described in the examples herein. Certain embodiments of the invention are illustrated in the following examples, which are not considered to be limiting: Example 1 Insulin (0.6 g) is dissolved in distilled water (50 mi) Diluent (14.4 g) is added and dissolved, then the pH is adjusted to 7.4. The solid cake obtained is milled, sieved and micronized in a jet mill. The micronized powders are agglomerated and supplied as a filler in a Turbuhaler dry powder inhaler and the dose is released at an air flow rate of 60 1 / min under various conditions.The eliminated dose is collected using a multiple cap impeller The insulin content in each stage of the impeller is determined using liquid chromatography with detection at 235 nm.The results are as follows. a pre a n o v u um uran e res on open plates.

It is clear that the melecitosa provides the highest fraction of respirable particles in all cases. In addition, the respirable fraction does not depend on external factors when used as a melecitosa diluent.

F. Example 2 Insulin (12 parts) is dissolved in distilled water. Sodium taurocholate (improver, 4 parts) is added. Various diluents (84 parts) are added and dissolved, and the pH is adjusted to 7.4. The solution is concentrated by evaporation of water. The solid cake obtained is milled, sieved and micronized in a jet mill. The micronized powder is agglomerated and supplied as a filler in a Turbuhaler ™ dry powder inhaler and the dose is released at an air flow rate of 60 1 / min, under varying conditions. The released dose is collected using a multiple-capped impeller; the insulin content in each stage of the impeller is determined using liquid chromatography with detection at 235 nm. The results are as follows.

The results show that the formulation with melecitosa is affected in a lesser way by the high humidity in the air.

Example 3 Micronized formulations containing DNase, surfactant (sodium taurocholate or dioctanoylphosphatidylglycerol) and melecitosa (ratio of DNase: surfactant: melecitose, 1: 0.33: 98.67, total weight, 50 mg) to propellant 134a or propellant 227 (approximately 10 ml) are added. in a glass jar and covered with plastic. The formulations are mixed with ultra turrax equipment for approximately 10 minutes.

Identical formulations are prepared to which 5% ethanol is added before mixing with an ultraturrax apparatus for about 10 minutes. The quality of the suspensions formed is determined immediately and after 20 hours. In all cases good suspensions were observed. This demonstrates that the melecitosa-containing formulations of the present invention are suitable for use in different dry powder inhalation formulations, in this case, in aerosol formulations. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, property is claimed as contained in the following:

Claims (8)

1. A powder formulation for the administration of medically useful polypeptides by inhalation, characterized in that it comprises a medically useful polypeptide with melezitose as a diluent.

2. The powder formulation according to claim 1, characterized in that the melecitosa comprises D-melecitosa (aD-melecitosa), β-D-glucopyranoside, OaD-glucopyranosyl-1,3-β-D-fructofuranosyl (β-D-melecitosa ) or isomelecitosa.

3. The powder formulation according to claim 1 or claim 2, wherein the melecitosa is in the form of monohydrate or dihydrate.

4. The powder formulation according to any of claims 1 to 3, characterized in that the formulation includes an enhancer which improves the absorption of the medically useful polypeptide in the lower respiratory tract.

5. The powder formulation, according to claim 4, characterized in that the improver is selected from C8-16 fatty acids and salts thereof, bile salts, phospholipids and alkyl saccharides.

6. The powder formulation, according to claim 4, characterized in that the improver is selected from sodium, potassium and cap salts (C8), caprate (C10), laurate (C12) and myristate (C14).

7. The powder formulation according to claim 4, characterized in that the enhancer is selected from bile salts which are selected from cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycokenedeoxycholic acid, taurokenedeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic, lithocholic acid and ursodeoxycholic acid.

8. The powder formulation according to claim 4, characterized in that the improver is selected from trihydroxy bile salts.