WO2017134655A1 - Improved oral absorption of octreotide and salts thereof - Google Patents

Abstract

The invention provides novel formulations of octreotide and encapsulated forms thereof.

Description

IMPROVED ORAL ABSORPTION OF OCTREOTIDE AND SALTS THEREOF

TECHNOLOGICAL FIELD

The invention generally provides a novel approach for improving oral absorption of octreotide and salts thereof.

BACKGROUND

The majority of peptide and protein drugs are still administered by injection, often causing pain-associated problems and major inconvenience to the patients. Hence, non-invasive delivery systems for such drugs are required. The oral route offers the advantage of self-administration with high patient compliance. However, poor membrane permeability of these macromolecules hampers oral, as well as other noninvasive administration routes. To enable effective transmucosal protein delivery, attention has focused on formulations that improve membrane absorption and prevent degradation. Biotech drugs are predicted to become the main source of therapeutics in the near future with the therapeutic exploitation of such molecules relying on the possibility to develop suitable formulations that can satisfactorily overcome the intrinsic limitations of their use; namely low oral bioavailability, biological and physicochemical instability.

Indeed, the oral route is considered to be the most convenient and comfortable route of chronic drug administration for patients. However, oral administration of protein drugs encounters many difficulties due to their proteolytic instabilities and limited abilities to traverse biological barriers.

Nano-sized systems (e.g., liposomes, lipid and polymeric nanoparticles, micelles, etc.) have been found to be advantageous over traditional formulations for oral protein delivery. Unfortunately, liposome and micelle-based delivery systems are not stable in the gut lumen and cannot elicit an adequate protection to these sensitive biomacromolecules. Therefore, among the pharmaceutical formulations, nanoparticles (NPs) have been explored and found to be successful for drug delivery of peptidic drugs. NPs, more specifically the biodegradable polymeric NPs, possess excellent biocompatibility, biodegradability, composition flexibility and small size, making them suitable for a variety of applications. Furthermore, these formulations have been shown to enhance the drug bioavailability following oral administration. Although encapsulation with biodegradable polymers is very attractive, the manufacturing processes are still complicated and expensive for hydrophilic macromolecules. In the case of efficient entrapment approaches of protein drugs into these systems, encapsulation using polymers may provide protection for the proteins from degradation during storage and delivery, as well as a sustained release profile when desired.

Recently, the improvement of oral bioavailability of GLP-1 analog peptides has been reported, relative to their subcutaneous counterpart, by 14.0+1.8%. Although this achievement is promising, it is much less than the minimal oral absolute bioavailability of 25-30%, which is still considered poor by the FDA for a drug to be administered orally.

Octreotide acetate is a potent synthetic somatostatin analogue that has become the mainstay of medical therapy in neuroendocrine disorders, such as acromegaly and carcinoid syndrome associated with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [1-4]. The development of octreotide acetate long-acting release offered a further advancement [5]. For drugs used for long-term treatment or prevention, such as octreotide acetate for portal hypertension in liver cirrhosis [6], oral administration is the preferred route. If oral administration could be applied clinically, it would be a safe and convenient method for patients with liver disease to prevent portal hypertension. Octreotide acetate has few side effects, and its injection is clinically used for lowering the portal hypertension associated with liver cirrhosis. The oral delivery of octreotide acetate would have important clinical significance of avoiding multiple daily injections for these patients. Recently, octreotide acetate has attracted a great deal of attention and study to improve its oral delivery [7, 8].

REFERENCES

[1] Melmed, S. N., Engl. J. Med., 2006, 355, 2558-2573

[2] Kleinberg, D.L., Rev. Endocr. Metab. Disord., 2005, 6, 29-37

[3] Bauer, W. et al, Life Sci., 1982, 31, 1133-1140

[4] Delaunoit, T. et al, Mayo. Clin. Proc, 2005, 80,502-506

[5] Anthony, L. et al., Curr. Med. Res. Opin., 2009, 25(12), 2989-2999

[6] Li, Y. et al., Int. J. Mol. Sci., 2013, 20,14(6),12873-12892 [7] Dorkoosh, F.A. et al, Pharm. Res., 2002, 19, 1532-1536

[8] Tuvia, S. et al, /. Clin. Endocrinol. Metab. 2012, 97, 2362-2369

[9] US 8,535,695

GENERAL DESCRIPTION

The inventors of the invention disclosed herein have developed a unique platform for improving oral bioavailability of octreotide and salts thereof. The present invention makes use of an oil formulation, capable of relatively high solubilization of octreotide and its salts. In the oil formulation, the octreotide is nano-encapsulated into nanocapsules, and further embedded into microparticles, such that the oral bioavailability of octreotide and its controlled delivery is improved, thereby providing a novel delivery platform which permit efficient oral delivery of octreotide or salts thereof. Although octreotide is a hydrophilic molecule, the inventors of the present invention have developed a lipophilic oil formulation in which relatively high solubilization of octreotide and its salts is achieved.

Thus, in one of its aspects, the invention provides an oil formulation comprising octreotide or a salt thereof, octanoic acid, and optionally oleic acid.

In another aspect, there is provided an oil formulation consisting of octreotide or a salt thereof and octanoic acid, and optionally further comprising oleic acid. In other words, in some embodiments, the formulation is a two-component system comprising octreotide and octanoic acid, or a three-component system comprising octreotide, octanoic acid and oleic acid.

In another aspect, the invention provides a carrier system comprising octreotide and at least one carrier for holding said octreotide, said at least one carrier being selected amongst known and available drug delivery systems. In some embodiments, the delivery system of the invention further comprises at least one liquid component, e.g., octanoic acid and/or oleic acid.

Whether as an oil formulation or as a carrier system, the formulation or system may comprise octreotide or a salt thereof, octanoic acid, and oleic acid. The oil formulation or system is such that the octreotide (or salt thereof) is solubilized within the octanoic acid and the oleic acid, such that a homogenous formulation is obtained.

The octreotide may be present in salt form. According to some embodiments, the salt is selected from octreotide acetate, octreotide pamoate, octreotide diacetate, octreotide trifluoroacetate (TFA octreotide), salts of octreotide with saturated fatty acids, and any other suitable octreotide salt known in the art. In such embodiments, the saturated fatty acid having a carbon chain length of C_8-i6.

According to some embodiments, the octreotide salt is octreotide acetate.

In some embodiments, the oil formulation is contained or comprised within or is part of a carrier system according to the invention.

In some embodiments, the oil formulations comprises between about 5 and about 125 mg/ml of octreotide or a salt thereof as the active ingredient. In other embodiments, the oil formulations comprises the active ingredient in an amount between about 10 and about 125 mg/ml, between about 20 and about 125 mg/ml, between about 30 and about 125 mg/ml, or between about 40 and about 125 mg/ml. In some other embodiments, the oil formulations comprises between about 5 and about 120 mg/ml, between about 5 and about 110 mg/ml, between about 5 and about 105 mg/ml, or even between about 5 and about 100 mg/ml of octreotide or a salt thereof.

As used herein, the "oil formulation" of the invention, or used in accordance with the invention comprises octreotide, octanoic acid and optionally oleic acid. In some embodiments, the ratio of octanoic acid to oleic acid may be between about 1:2 and 1 :4 (wt/wt). In other embodiments, the ratio of octanoic acid to oleic acid is between about 1:2.5 and 1 :3.5 (wt/wt), In other embodiments, the ratio of octanoic acid to oleic acid is about 1:3 (wt/wt).

In order to, e.g., facilitate formation of nanocapsules, as disclosed herein, the oil formulation may, in some embodiments, further comprise at least one surfactant. The surfactant used in accordance with the invention n may be any agent capable of lowering surface tension of a liquid, allowing for the formation of a homogeneous mixture of at least one type of liquid with at least one other type of liquid, or between at least one liquid and at least one solid. Thus, surfactants used in the oil formulation of the invention may be used to control the surface tension and surface interaction between the oil formulation and its surroundings, e.g., thereby assisting in the process of forming the nanocapsules. Non-limiting examples of suitable surfactants are oleoyl polyoxyl-6- glycerides NF (Labrafil M1944 CS, Gatefosse), and other nonionic oil surfactants having a hydrophilic-lipophilic balance (HLB) value between 8 and 10, such as Brij® L4 (average M_n~362), MERPOL® SE, poly(ethylene-glycol) sorbitol hexaoleate, poly(ethyleneglycol)-block-poly(propyleneglycol)-block-poly(ethyleneglycol) (average Mn~5,800), Labrafil® M2125CS, Labrafil® M2130CS, Tefose 63, sorbitan monoesters (sorbitan monolaurate=Span 20) and PEG-4 sorbitan monostearate (Tween 61)

The invention further provides octreotide or a salt thereof in an encapsulated form. The encapsulated product is a microparticle encapsulating a plurality of nanocapsules (i.e. two or more nanocapsules), at least one of said plurality of nanocapsules containing octreotide or a salt thereof. The term "encapsulation" (or any lingual variation thereof) refers to the containment of octreotide in a nanocapsule, or the containment of at least one nanocapsule within a microparticle as will be further explained.

Thus, in another one of its aspects, the invention provides a nanocapsule comprising octreotide or a salt thereof, the nanocapsule comprising a core and a hydrophobic encapsulation shell, the core comprising an oil formulation as described herein. In some embodiments, the nanocapsules are contained, carried or encapsulated in at least one liquid or solid carrier selected from a liquid medium or a micro or nanoparticle.

As may be understood, while the octreotide oil formulation is contained in the core region of the nanocapsule, some of the oil formulation, including the octreotide, may also be present in the hydrophobic shell. In some embodiments, the presence of the oil formulation and the active octreotide is limited or restricted to the core of the nanocapsule.

The invention further provides a nanocapsule comprising octreotide or a salt thereof for use in the formation of a microparticle, the microparticle comprising a core and a hydrophobic encapsulation shell, the core comprising an oil formulation of octreotide or a salt thereof and octanoic acid. In some embodiments, the oil formulation of octreotide or a salt thereof and octanoic acid are contained in nanocapsules that are contained or further encapsulated in a particle, which may be a nanoparticle or a microparticle.

Further provided is a nanocapsule for use in a method of preparation of a microparticle, the nanocapsule comprising a core and a hydrophobic encapsulation shell, the core comprising octreotide or a salt thereof and octanoic acid. In some embodiments, the microparticle comprising or being constructed of a hydrophilic material, e.g., a hydrophilic polymer. Thus, the carrier systems of the invention, for carrying octreotide or a salt thereof, are selected from:

1. Formulations comprising octreotide and/or a salt thereof and octanoic acid;

2. Formulations consisting octreotide and/or a salt thereof and octanoic acid;

3. Formulations comprising octreotide and/or a salt thereof and octanoic acid and optionally further oleic acid;

4. Formulations consisting octreotide and/or a salt thereof, octanoic acid and oleic acid;

5. Nanocapsules or nanoparticles comprising octreotide and/or a salt thereof and octanoic acid, and optionally further oleic acid;

6. A population of nanocapsules or nanoparticles comprising octreotide and/or a salt thereof and octanoic acid, and optionally further oleic acid; wherein the population is contained in at least one carrier system, the system being a liquid or a solid system, e.g., a microparticle;

7. A microparticle comprising a population of nanocapsules or nanoparticles containing, comprising or consisting octreotide and/or a salt thereof and octanoic acid, and optionally further oleic acid.

Each of the carrier systems of the invention may be used in accordance with embodiments of the invention.

A method for preparing such nanocapsules as described herein also constitutes an aspect of the invention. The method comprises:

mixing (i) an oil formulation comprising octreotide or a salt thereof, and octanoic acid with (ii) a solution of a hydrophobic polymer in a solvent, to thereby form an organic phase; and

adding water to said organic phase under conditions permitting the formation of said nanocapsules.

In some embodiments, an oil formulation comprising octreotide, octanoic acid and optionally oleic acid is prepared.

In some embodiments, an organic phase is obtained by mixing the oil formulation with a solution of a hydrophobic polymer in a solvent, such as, for example, a polar solvent which can substantially solublize the hydrophobic polymer and also exhibit good solubility in water. In some embodiments, the solvent may be an organic solvent, e.g., selected from acetone, ethanol and mixtures thereof, or may be generally a non-aqueous solvent. Once a homogenous organic phase is obtained, water is added under conditions permitting formation of a hydrophobic shell around octreotide - containing oily cores, thus obtaining the nanocapsules. In some embodiments, the volume ratio between the organic phase and the aqueous phase may be between about 1 :3 and 1 :5.

The conditions permitting formation of the hydrophobic shell may include, for example, drop-wise or slow addition of the water into the organic phase, mixing at a predetermined speed (for example 500-1500 rpm), etc. The process is typically carried out at a temperature below 30°C. In some embodiments, the process is carried out at a temperature between 10 and 30°C, or between 10 and 25°C, or between 10 and 20°C, or between 10 and 15°C, or between 15 and 30°C, or between 15 and 25°C, or between 15 and 20°C, or between 18 and 30°C, or between 18 and 25°C.

The "nanocapsule" (NC) of the invention is a particulate carrier, being nanoparticle in shape and size, having distinct core and shell components, which is biocompatible and sufficiently resistant to chemical and/or physical destruction, such that a sufficient amount of the nanocapsules remains substantially intact after administration into a human or animal body and for a sufficient period of time to reach a desired target organ (tissue). Generally, the nanocapsules are spherical in shape, having an average diameter of up 500 nanometers (nm). In some embodiments, the averaged diameter of a nanocapsule is at least about 50 nm.

In some embodiments, the averaged diameter of a nanocapsule is between about 50 and 500 nm, 100 and 500 nm, 150 and 500 nm, between about 200 and 500 nm, between about 250 and 500 nm or even between about 300 and 500 nm. In other embodiments, the averaged diameter is between about 100 and 450 nm. In other embodiments, the averaged diameter is between about 100 and 400 nm. In some other embodiments, the averaged diameter is between about 150 and 250 nm.

It should be noted that the averaged diameter of nanocapsules may be measured by any method known to a person skilled in the art. The term "averaged diameter" refers to the arithmetic mean of measured diameters, wherein the diameters range ±25%, ±15%, ±10%, or ±5% of the mean. Where the nanocapsules are not spherical, the term refers to the effective average diameter being the largest dimension of the nanocapsule. A nanocapsule of the invention is constituted by a core comprising an oil formulation of octreotide (or a salt thereof), octanoic acid and optionally oleic acid. The core is encapsulated by a hydrophobic layer, that forms a nanocapsule about the oily core.

As a person versed in the art would understand, "hydrophilicity" of materials is a characteristic defining affinity for water, while "hydrophobicity" of materials defines the material opposite response to water. The material hydrophobicity or hydrophilicity may be due to the material intrinsic behavior towards water, or may be achieved (or tuned) by modifying the material by one or more of cross-linking group or bond or association, with another material or between regions of the same material, derivatization of the material, charge induction to said material (rendering it positively or negatively charged), complexing or conjugating said material to another material or by any other means known in the art. In accordance with the present invention, the selection of a material may be based on the material intrinsic properties or based on the material ability to undergo such aforementioned modification(s) to render it more or less hydrophobic or hydrophilic.

As noted above, the encapsulation shell comprises, is made of, or at time is constituted by a hydrophobic material, typically at least one hydrophobic polymer that is arranged as a film or a coat or a shell or an enclosure around a central region, i.e., a core. In some embodiments, the polymeric shell is a shell encapsulating the active material, i.e., octreotide and/or its salts and the additional components, as disclosed herein.

In some embodiments, the hydrophobic polymer is any such polymer having a molecular weight of between about 2,000 and 100,000 Da.

The shell may be made of or comprise or consist at least one hydrophobic polymeric selected from lactic acid, poly(D,L-lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PLA), poly(e-caprolactone), poly(2-dimethylamino- ethylmethacrylate) homopolymer, poly(2-dimethylamino-ethylmethacrylate)-b-poly (ethyleneglycol)-a-methoxy-ro-metahcrylate copolymers, polycyanoacrylates, PEGylated derivatives of any one of the aforementioned polymers, or a combination of any of the polymers. In some embodiments, the encapsulation polymeric shell comprises a polymer selected from lactic acid, poly(D,L-lactic-co-glycolic acid) (PLGA) and combinations thereof, including mixtures with PEGylated derivatives thereof.

In some embodiments, the polymeric shell comprises or consists lactic acid and/or poly(D,L-lactic-co-glycolic acid) (PLGA).

In some embodiments, the polymer having a molecular weight of between about 2,000 and 100,000 Da is any one or more of lactic acid, poly(D,L-lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PLA), poly(e-caprolactone), poly(2- dimethylamino-ethylmethacrylate) homopolymer, poly(2-dimethylamino- ethylmethacrylate)-b-poly (ethyleneglycol)-a-methoxy-ro -metahcrylate copolymers, polycyanoacrylates, PEGylated derivatives of any one of the aforementioned polymers, or a combination of any of the polymers.

In order to improve the oral bioavailability of octreotide, the nanocapsules may be further encapsulated in a larger carrier, such as a microparticle, the microparticle comprising or consisting polymers which enable controlled release of the nanocapsules in the gastrointestinal (GI) tract to permit control and sustained release of octreotide by oral administration.

Thus, in another of its aspects, the invention provides a microparticle comprising at least one nanocapsule as herein defined (i.e. a nanocapsule comprising an octreotide - containing oil core and a hydrophobic shell), the microparticle being optionally embedded in a hydrophilic polymeric matrix.

In other embodiments, the microparticle is carried in a liquid or solid carrier, the solid carrier being in powder form or in a continuous matric form.

The microparticle (used interchangeably with microsphere) is a micron- or submicron particle of a substantially uniform composition, constituted by a continuous material, i.e. not featuring a distinct core/shell structure. The microparticles may be solid or semi-solid, e.g. in partially gelled form.

Generally speaking, the microparticles of the invention should be large enough to be able to hold at least one nanocapsule, at times a plurality of nanocapsules, and at the same time be sufficiently small size to be able to undergo internalization. In some embodiments, the microparticles have an average diameter of between about 0.5 and 20 μπι. In other embodiments, the microparticles have averaged diameter of between about 0.5 and 15 μπι, between about 0.5 and 10 μπι, or between about 0.5 and 5 μπι. In further embodiments, the averaged diameter is between about 1 and 12 μιη. In additional embodiments, the microparticles have averaged diameter of between 1 and 8 μιη.

The number of nanocapsules which are encapsulated within a single microparticle according to the invention may vary depending on, e.g., the size of the nanocapsule or the relative sizes of the nanocapsule and the microparticle. Typically, each microparticle may contain between 1 and a few (6-7) dozens of nanocapsules (being an example of a plurality of nanocapsules). In some embodiments, each microparticle comprises between 2 and 50 nanocapsules, between 2 and 40 nanocapsules, between 2 and 30 nanocapsules, or even between 2 and 20 nanocapsules. In some embodiments, each microparticle comprises between 2 and 10 nanocapsules.

The microcapsules of the invention may encapsulate a plurality of nanocapsules of different materials and/or different active agents, provided that at least of one of the nanocapsules encapsulates the octreotide-containing oil formulation of the invention. The microparticles of the invention, for example, may contain a plurality of nanocapsules of the same polymeric material (thus having the same hydrophilic/hydrophobic properties), some of which comprising the oil formulation of the invention and the other comprising one or more different active agents. Similarly, the microparticles of the invention may contain a plurality of nanocapsules of different polymeric materials, however containing each the oil formulation of the invention. Each of the nanocapsules may comprise varying forms of octreotide or salts thereof, at the same or different concentration.

In the microparticles of the invention, the octreotide-encapsulating nanocapsules are embedded within a hydrophilic polymeric matrix; meaning that the nanocapsules are distributed within the matrix material of the microparticle, and are substantially fully encased thereby or embedded therein. Once in the GI tract, the hydrophilic polymer permits (i.e. by dissolution, decomposition or swelling) release of the embedded nanocapsules for controlled and sustained delivery of octreotide via the GI mucosal tissue.

Unlike the hydrophobic shell of the nanocapsules, the microparticles are made of a hydrophilic polymer that makes-up the full volume of the microparticles and thus acts as a matrix or carrier material for fully holding, embedding or encapsulating the plurality of nanocapsules. The hydrophilic polymer is either a single polymer or a blend of polymers, which have the tendency to undergo a physical and/or chemical change, i.e. dissolution, decomposition, swelling, etc., due to interaction with aqueous surroundings. In some embodiments, the hydrophilic polymer undergoes a desired change once exposed to an aqueous surroundings, or at a desired pH.

In some embodiments, the hydrophilic polymer is an enteric polymer (or polymer blend). Enteric polymers are typically insoluble in environments of low pH, and dissolve or form hydrogels at higher pH conditions. A typical pH threshold for enteric polymers is pH 4-5, which provides protection of the nanocapsule (and therefore also of the octreotide) from undesired decomposition due to the extremely acidic conditions of the stomach, thereby assisting in controlled and improved oral delivery of the octreotide.

In some embodiments, the hydrophilic polymer is selected from poly(methacrylic acid), ethyl acrylate, polyols, polycarbohydrates, hydroxypropylmethyl cellulose (HPMC), hydroxymethyl cellulose, hydroxypropylmethylcellulose phthalate (HP55), cellulose acetate phthalate, carboxy- methylcellulose phthalate, and copolymers and mixtures thereof.

In other embodiments, the hydrophilic polymer comprises a HPMC:Eudragit (poly(methacrylic acid) -ethyl acrylate copolymer) blend. In such a Eudragit:HPMC blend, the Eudragit has a pH-dependent solubility, and HPMC is water-soluble, irrespective of the pH.

As used herein, either in connection with the nanocapsule or the microparticle, the term "polymer" includes homopolymers, copolymers, such as for example, block, graft, random and alternating copolymers as well as terpolymers, further including their derivatives, combinations and blends. In addition to the above, the term includes all geometrical configurations of such structures including linear, block, graft, random, alternating, branched structures, and combination thereof.

The polymers utilized in the construction of the nanocapsules and microparticles of the invention are biodegradable, namely, they degrade during in vivo use. In general, degradation attributable to biodegradability involves the degradation of a biodegradable polymer into its component subunits, or digestion, e.g., by a biochemical process carried out for example by enzymes, of the polymer into smaller, non-polymeric subunits. The degradation may proceed in one or both of the following: biodegradation involving cleavage of bonds in the polymer matrix, in which case, monomers and oligomers typically result, or the biodegradation involving cleavage of a bond internal to side chain or that connects a side chain to the polymer backbone. In some embodiments, biodegradation encompasses both general types of biodegradation. The polymers are additionally biocompatible, namely, they are substantially non-toxic or lacking injurious impact on the living tissues or living systems to which they come in contact with.

In another aspect, the invention provides a method of preparing microparticles as herein described, the method comprising:

mixing (i) a suspension of nanocapsules as herein described with (ii) an aqueous solution of at least one hydrophilic polymer to obtained a mixed suspension; and

transforming the mixture into microparticles (namely, micronizing the mixed suspension).

In some embodiments, the microparticles are formed by atomizing or spraying or any method known in the art. In some embodiments, the microparticles are formed by spray drying the mixed suspension. As known in the art, spray drying comprises transporting (e.g., delivering, spraying) a colloidal composition (i.e. the mixed suspension), comprising a plurality of the nanocapsules and a microparticle-forming material e.g., the hydrophilic polymeric material, under conditions permitting formation of micronized droplets (i.e. in the sub-micron or micron scale). These droplets may be formed, for example, by atomizing, spraying, etc. The size of droplets that are formed by said spray drying determines the (maximal) size (diameter) of the microparticles.

In some embodiments, the method may further comprise drying the microparticles obtained. The drying step may be achieved by evaporation of the media solvents by, for example, lyophillization, thermal drying, reduced pressure, solvent extraction and other techniques.

According to some embodiments, the at least one hydrophilic polymer is an HPMC:Eudragit (poly(methacrylic acid)-ethyl acrylate copolymer) blend. In such embodiments, the aqueous solution may have a pH of about 5.5-6.5 in order to permit satisfactory dissolution of the Eudragit. The pH in the aqueous solution may be, by some embodiments, controlled by the addition of at least one buffer solution.

According to another aspect, the invention provides a method of preparing a microparticle comprising octreotide or a salt thereof, the process comprising: mixing (i) an oil formulation comprising octreotide or a salt thereof, octanoic acid and optionally oleic acid, with (ii) a solution of a hydrophobic polymer in a solvent, to thereby form an organic phase;

adding water to said organic phase under conditions permitting formation of a nanocapsules suspension, the nanocapsules comprising a core of said oil formulation and an encapsulation shell comprising said hydrophobic polymer;

mixing said suspension of nanocapsules with an aqueous solution of at least one hydrophilic polymer to obtained a mixed suspension; and

micronizing the mixed suspension, e.g., by spray drying, to thereby obtain said microparticles.

In another one of its aspects the invention provides a pharmaceutical composition comprising at least one microparticle of the invention as herein described and at least one pharmaceutically acceptable carrier or excipient.

The "pharmaceutically acceptable carriers" described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compound(s) and one which has no detrimental side effects or toxicity under the conditions of use.

The choice of carrier will be determined by a variety of factors. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, parenteral, intravenous, intramuscular, or intraperitoneal administration or formulations for delivery intranasally or by inhalation are merely exemplary and are in no way limiting.

The pharmaceutical composition is prepared in a manner well known in the pharmaceutical art. In making the pharmaceutical composition of the invention, the aforementioned components are usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be manipulated to the desired form.

In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In such embodiments, the pharmaceutical composition may be selected from a powder, a tablet, a capsule, a granule, a pill, a lozenge, a troche, a sachet, a chewing gum, and a suspension.

Suspension formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active formulation in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active formulation, such carriers as are known in the art.

In some embodiments, the pharmaceutical composition of the invention, independent of the mode of administration, may be engineered or adaptable for immediate release, sustained release, controlled release, slow or fast release, pulsatile release or any other facilitated of a therapeutically effective amount of octreotide or a salt thereof.

As known, the "effective amount" of octreotide or a salt thereof, contained in a composition or formulation or medicament according to the invention may be determined by such considerations as known in the art. The amount of octreotide or a salt thereof must be effective to achieve the desired therapeutic effect, depending, inter alia, on the type and severity of the disease to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, the effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, on factors such as age and gender, and others.

In another aspect, the invention provides a carrier system, as defined herein, e.g., in the form or a microparticle (or a composition comprising microparticles) for use in oral delivery of octreotide or a salt thereof to a subject in need thereof.

A further aspect provides use of a carrier system, as defined herein, e.g., in the form or a microparticle (or a composition comprising microparticles) for the preparation of a medicament for oral delivery of octreotide or a salt thereof.

Yet a further aspect provides a method of administration of octreotide or a salt thereof to a person in need thereof, comprising orally administering to the subject a carrier system, as defined herein, e.g., in the form or a microparticle (or a composition comprising microparticles), as herein described.

The carrier system, as defined herein, e.g., in the form or a microparticle (or a composition comprising microparticles) may be used as such to induce at least one effect, e.g., "therapeutic effect" , or may be associated with or conjugated to at least one other agent to induce, enhance, arrest or diminish at least one effect or side effect, by way of treatment or prevention of unwanted conditions or diseases in a subject. The at least one other agent (substance, molecule, element, compound, entity, or a combination thereof) may be selected amongst therapeutic agents, i.e., agents capable of inducing or modulating a therapeutic effect when administered in a therapeutically effective amount, and non-therapeutic agents, i.e., which by themselves do not induce or modulate a therapeutic effect but which may endow the nanoparticles with a selected characteristic, as will be further disclosed hereinbelow.

The subject to be treated may be human or non-human.

The carrier system, as defined herein, e.g., in the form or a microparticle (or a composition comprising microparticles) may be utilized to treat, prevent or diagnose any pathology or condition. Where treatment or prophylactic modalities are concerned, the carrier system may be used in connection with such a pathology or condition known to be treated by administration of octreotide or a salt thereof. The term "treatment" or any lingual variation thereof, as used herein, refers to the administering of a therapeutic amount of the composition or a formulation or a medicament (generally- a carrier system) of the present invention, which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.

In another aspect, the invention also provides a kit or a commercial package containing the pharmaceutical composition of the invention as herein described, and instructions for use. In some embodiments, the composition of the invention or a fraction derived therefrom may be present in the kit in separate compartments or vials.

The kit may further comprise at least one carrier, diluent or solvent useful for the preparation of the composition. The composition may be prepared by the end user (the consumer or the medical practitioner) according to the instructions provided or the experience and/or training of the end-user.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

Fig. 1 is a SEM microphotograph of Batch OCT-A MCPs pooled from batches 3, 5 and 8, the properties of which are described in Table 3. The size of the MCP appears homogeneous and the diameter ranged from 2 to 5 μπι with many pores on the surface of the MCPs.

Fig. 2 shows average octreotide acetate plasma levels in SD male rats following oral administration of 1.5 mg/kg of octreotide acetate as microparticulated nanocapsules and subcutaneous injection of 1 mg/kg as a solution.

DETAILED DESCRIPTION OF EMBODIMENTS

Materials

PLGA (Lactel end capped hexandiol, 50:50 intrinsic viscosity 0.15-0.25 dL/g), Poly(methacrylic acid), Ethyl acrylate 1 : 1 (Eudragit® L100-55) was obtained from Evonik Rohm (Kirschenallee, Germany). Hydroxypropylmethylcellulose (Methocel E4M Premium) was purchased from Dow Chemical Company (Midland, MI, USA). Oleic acid was purchased from Fisher Scientific UK. Octanoic acid was purchased from Merck KGaA (Germany). Sodium phosphate monobasic, monohydrate was purchased from Mallinckrodt Chemicals (Phillipsburg, NJ, USA). Phosphate buffered saline was obtained from Biological Industries (Kibbutz Beit Haemek, Israel). All organic solvents were HPLC grade and purchased from J.T. Baker (Deventer, Holland). Octreotide acetate purchased from Novotide.

Methods

Solubility of octreotide acetate in various organic solvents

One milliliter of each solvent was added to 1 mg of lyophilized octreotide acetate salt, and vigorously vortexed for one minute and then stirred by shaking at 100 rpm for 24 hours. After 24 hours, the solubility of octreotide acetate in each solvent was visually monitored and evaluated.

Surprisingly, the only oil solvent that was able to dissolve the peptide and be used as the oil core of the nanocapsule was octanoic acid as shown below.

Preparation of nanocapsules

The primary NCs were prepared by dissolving in 100 mL of acetone: 300 mg of PLGA (Lactel end capped hexandiol 50:50 intrinsic viscosity 0.15-0.25 dL/g). In separate glass vials, 25 mg of octreotide acetate were dissolved in 120 mg of octanoic acid with vortex for 5 minutes at room temperature. To the same vial, 380 mg of oleic acid and 100 mg of Labrafil M 1944 CS were added and then vortexed vigorously for 2 minutes until complete dissolution. The contents of the vial were transferred to the acetone solution and washed three times with acetone to confirm that all the oil solution was added to the acetone-PLGA solution. 70 mL of bi-distilled water were slowly added to the organic phase while stirring at 1000 rpm until an O/W (oil-in- water) dispersion formed (NCs suspension).

Microencapsulation of the nanocapsules

To prepare double-coated formulations, a 150mL 5 mM sodium phosphate buffer was prepared; pH was adjusted to 6.5 by IN NaOH solution. 750 mg of Eudragit L were dissolved in this solution maintaining pH at 6.5. 100 mL of 1% HPMC solution were added. The combined solutions were added to the NC dispersed mixture. After combining the two suspensions, 80mL of bi-distilled water were added and acetone was evaporated using Laborta 4000 evaporator at room temperature under stirring (90rpm). After evaporation, the final suspension was diluted to 500 mL with bi-distilled water and filtered through a gauze pad.

The PLGA suspension was spray-dried with a Buchi mini spray-dryer B-290: Inlet temperature 110°C; outlet temperature ranged from 50 to 70°C; aspiration 100%; pump rate 20% (3.33 mL/min); nozzle cleaner 2 and air flow 601 L/h. The powder consisting of NCs embedded in spherical microparticles was collected and weighed. Various formulations were prepared as described above.

Drug content in microparticles

Extraction method: 10-15 mg of the unknown powder were added to 0.5 mL DMSO and stirred for 2 hours at 2500 rpm. Then 0.5 mL acetonitrile (ACN) were added and stirred for another 0.5 hour at the same speed. After complete dissolution 400 \iL were withdrawn from the DMSO-ACN solution and added to 1600 \iL of ACN and centrifuged for 2 min at 14000 rpm.

One milliliter from the clear supernatant was taken and used for analysis by HPLC accordingly: gradient of acetonitrile and TFA 0.1% from 0% to 100% TFA for 18 min, in a flow rate of 1 mL/min. The column is Luna C18. UV: 210 nm.

Preliminary in-vivo experiment with octreotide acetate

A first group of rats received octreotide acetate, s.c. at a dose of lmg/kg, meaning 0.35mg/rat (according to weight measurements). For the purpose of s.c. injection, the peptide was dissolved in isotonic acetate buffer pH 4.5 (the commercial vehicle of Sandostatin). The injection volume was 200 \iL. A second group received a mix of OCT-3, 5 & 8 batches at a dose of 1.5 mg/kg, meaning 0.525mg/rat.

As the content of the united formulations was 0.438 mg per 100 mg powder, a 1190 mg of the powder were suspended in 32 mL of DDW and then 4 mL of the suspension were orally administered to each rat in two doses by gavage with 5 minute intervals between each dose. One-mL blood samples were withdrawn at each time interval (1, 2, 4 and 8 hours) from the tail; collected in heparinized tubes, and centrifuged at 5000 rpm for 10 minutes. Then the plasma fraction was collected and transferred to clean tubes and kept at -80°C until analysis by LC-MS at Analyst Research Laboratories according to the method described below.

Octreotide acetate salt (Novotide, Lot no. 90048-11-294) with peptide content of 80.6 and purity of 99.6 % (HPLC) of octreotide acetate was used for primary stock solution preparation (300 μg/mL in methanol).

The primary stock solution was serially diluted with methanohwater 1 :9 and added to blank rat plasma (ratio 1:50) to produce final concentrations of 1, 2, 10, 30, 200, 450 and 500 ng/mL (nominal) for calibration curve standards and 3, 20, 100 and 400 ng/mL (nominal) for QC samples. Calibration standards and QC aliquot samples were immediately transferred to storage at -70°C (nominal). One set of standards and QC samples were freshly prepared on the day of spiking. Frozen samples were thawed at room temperature. Samples were processed at room temperature. A blank sample (blank plasma) and blank reagent (water) were also prepared. To 200 aliquots of each sample, calibrator, and QC sample, 1000 μί of acetonitrile:formic acid 99: 1 solution were added and then vortex mixed for 30 seconds. The sample was then centrifuged for 5 minutes at 14000 rpm at 5°C. 1000 of the upper (organic) layer was transferred into evaporation tubes and then evaporated under N2 stream at -50°C. Samples were then reconstituted with 300 μί reconstitution solution (water: acetonitrile: formic acid 70:30:0.1), mixed and then centrifuged at 4000 rpm for 5 minutes. 160 μL of the sample solution was transferred into an autosampler vial with a conic glass insert, and then analyzed by LC-MS/MS

Chromatographic conditions were as follows: HPLC instrument: Waters 2795 Alliance HT with temperature-controlled autosampler, Column: XBridge 100x2.1 mm, 3.5 μ, Waters® C8 110A, P.N. 186003048, with an appropriate guard column.

Column temperature: 45°C Sample temp.: 5°C; Mobile phase A: water:acetonitrile:formic acid 90: 10:0.1 ; Mobile phase B: water: acetonitrile: formic acid 10:90:0.1.

Wash solvent: water:acetonitrile 10:90; Purge solvent: water:acetonitrile:formic acid 70:30:0.1. Injection volume was 20 μL· and run time, 7 min. The solvent gradient conditions of the HPLC analysis is provided in Table 1. Time (min ) % A %B Flow

0.00 100 0 0.25

3.00 30 70 0.25

4.40 30 70 0.25

4.50 0 100 0.25

5.50 0 100 0.25

5.60 100 0 0.25

Tal )le 1: HPLC Gradient conditions

Detection was based on electro-spray interface in positive mode (ESI+) LC- MS/MS technique, using Micromass Quattro Pt MS/MS detector with MassLynx and QuanLynx software version 4.1. MRM transitions for octreotide acetate was m/z 510.4 - 120.1.

Results

Solubility of octreotide acetate

The following solubility parameters are for 1 mg Octreotide acetate in 1 mL solvent/oil, unless otherwise indicated. Tables 2.1-2.3 show the solubility of Octreotide acetate in various solvents.

Table 2.2: Solubility in organic solvents

Table 2.3: Solubility in oils

*as 1 mg of octreotide acetate was completely soluble in 1 ml of octanoic acid, more of the peptide was added until complete solubility. From further experiments, the maximum solubility of octreotide acetate in octanoic acid is 125mg/ml.

The high solubility of octreotide acetate in octanoic acid was not expected in view of the low solubility of the peptide in other oil solvents as shown in Table 2.3.

It should be emphasized that this finding is of importance as only oils can serve as core cargo for nanoencapsulation of octreotide acetate in the delivery system of the invention.

Physicochemical characterization

Apparent

Zeta Octreo.

Size DI yield of

Formulation Octreotide acetate potential Cont.

(nm) value encapsul.

(mV) (%w/w)

(%)

NCs in

326.4+2. 0.23 -32.2+0.4

0 aqueous disp.

BLK-OCT-1 - -

(mg) NCs+Eud.+

538.1+19.5 0.26 -12.2+0.66

HPMC

NCs 330.4+21.5 0.31 -36.2+0.608

5

OCT-2 NCs+Eud.+ 0.056 31.4

(mg) 632.9+8.9 0.28 -7.87+0.894

HPMC

NCs 416.2+14.1 0.47 -36.3+0.36

25

OCT-3 NCs+Eud.+ 0.426 47.8

(mg) 780.4+8.5 0.32 -6.64+0.219

HPMC

NCs 380+19 0.31 -35.1+0.97

25

OCT-4 NCs+Eud.+ 0.990 102.7

(mg) 600.1+9.7 0.21 -7.7+0.15

HPMC

NCs 498+8.9 0.36 -43.9+0.66

25

OCT-5 NCs+Eud.+ 0.434 49.3

(mg) 751.1+54.9 0.47 -6.28+0.54

HPMC NCs 407.2+4.8 0.28 -47.1+2.80

0

BLK-OCT-6 NCs+Eud.+ - -

(mg) 455.7+17.1 0.22 -6.14+0.42

HPMC

NCs 349.7+11.7 0.31 -38.6+0.75

25

OCT-7 NCs+Eud.+ 0.330 39.5

(mg) 589.5+14.6 0.21 -5.88+0.36

HPMC

NCs 398.7+22.1 0.265 -38.4+1.77

25

OCT-8 NCs+Eud.+ 0.456 51.5

(mg) 524.4+12.8 0.251 -4.02+0.26

HPMC

Table 3: Physicochemical properties and drug content of various octreotide acetate formulations

The data are presented in Table 3.

Animal study of octreotide acetate absorption in rats

Three batches (3, 5 and 8 in Table 4) were pooled together and entitled OCT-A. The octreotide acetate content in the microparticles ranged from 0.426 up to 0.456 % w/w. The final octreotide acetate content of the pooled batches was 0.438% in the final dry powder.

Table 4: Formulation reference tested in the preliminary PK experiment

Rats I- VI were orally administrated with a formulation of nanocapsules containing octreotide acetate encapsulated in microparticles-OCT-A. Dose: 1.5mg/kg (0.525mg/rat). Rats 1-6 were subcutaneously injected with octreotide acetate. Dose: lmg/kg (0.35mg/rat). All samples are in plasma.

Animal Time

Group Cone. ng/niL

number point

OCT-A I lh 130.12 4h 158.00

lh 145.27

II

4h 57.02

lh 149.72

III

4h 77.94

2h 4.59

IV

8h 123.36

2h 6.53

V

8h 1.59

2h 5.07

VI

8h 71.31

lh 560.55

1

4h 183.64

lh 429.16

2

4h 167.99

lh 395.77

3

4h 158.35

OCT-IM

2h 503.25

4

8h 6.44

2h 406.82

5

8h 3.90

2h 387.97

0

8h 9.23

Table 5: Octreotide acetate levels in rat's plasma at each time interval

Table 6: The AUC Values and calculated bioavailability values of octreotide acetate normalized to the dose

Prior research has shown that sinomenine could improve the intestinal absorption rate and oral bioavailability of octreotide acetate in rats [9]. Compared to IV injection, the oral bioavalability of octreotide acetate alone was 1.63+0.31 and with 0.5% sinomenine, the oral bioavailability increased to 8.67+1.73%.

Published studies using alternative oral absorption enhancers able to open non- specifically the tight junctions such as Intravail^®, a family of patented alkyl saccharide transmucosal absorption-enhancing agents significantly enhanced the total uptake following oral delivery of octreotide acetate in 0.5% Intravail® (1254.08 ng/ml/min vs. 311.63 ng/ml/min, respectively), serum half-life (52.1 min vs. 1.3 min, respectively), and relative bioavailability (4.0 vs. 1.0, respectively) when compared to delivery by SC injection. However, higher concentrations of Intravail® did not further enhance uptake, serum half-life, or bioavailability. The results of this study indicate that oral delivery of octreotide acetate in Intravail® is feasible, but using alkylsaccharides which have been shown to transiently open tight junctions, thus increasing paracellular absorption non- specifically, can induce toxic effects and can render them much dependent on food intake. In addition, reproducibility remains an issue for such an approach. Nevertheless, as previously stated up to now, no oral octreotide acetate product based on such technology has been marketed. In addition, more recently other authors have tried to enhance the absorption of octreotide acetate via a suspension comprised of an admixture in a solid form of octreotide acetate and at least one salt of a medium chain fatty acid and a hydrophobic medium, e.g. castor oil or glyceryl tricaprylate or a mixture thereof.

The pharmaceutical compositions described herein contained medium chain fatty acid salts including octanoic acid and were substantially free of alcohols. The relative bioavailability of octreotide acetate in rats, pigs and monkeys was very low - in the range of 1 to 5%. It is not surprising that despite all the investigative efforts, the oral bioavailability of octreotide acetate could not be markedly improved owing mainly to the inability of the previous formulations to retain the hydrophilic active macromolecule under sink conditions in the gastrointestinal tract and more particularly in the intestine. Formulations of the invention not only provide an additional protective coating by embedding the nanocapsules within microparticles, but also the coating of the microparticles with a blend of polymers: a bioadhesive polymer (HPMC) and a gastro resistant polymer (Eudragit L-55) which would promote the passage of the nanocapsules through the enterocytes. As the test results above clearly show, marked improvement of the oral bioavailability of octreotide acetate is obtained with composition of the invention, suggesting that octreotide acetate-loaded nanocapsules penetrated the enterocytes. Without wishing to be bound by theory, nanocapsules comprising the oil composition of the invention, once internalized in the enterocytes, are transformed into lipoproteinated drug nanocarriers and behave like chylomicrons.

Claims

CLAIMS:

1. A nanocapsule for use in a method of preparation of a microparticle, the nanocapsule comprising a core and a hydrophobic encapsulation shell, the core comprising octreotide or a salt thereof and octanoic acid.

2. The nanocapsule of claim 1 , wherein the core further comprises oleic acid.

3. The nanocapsule of claim 1 or 2, wherein said octreotide salt is selected from octreotide acetate, octreotide pamoate, octreotide diacetate and octreotide trifluoroacetate (TFA octreotide).

4. The nanocapsule of claim 1 or 2, wherein said octreotide salt is selected from salts of octreotide and saturated fatty acids.

5. The nanocapsule of claim 4, wherein said saturated fatty acid having a carbon chain between 8 and 16 carbon atoms.

6. The nanocapsule of claim 3, wherein octreotide salt is octreotide acetate.

7. The nanocapsule of any one of claims 1 to 5, wherein said core comprises an oil formulation comprising between about 5 and 125 mg/ml of octreotide or a salt thereof.

8. The nanocapsule of claim 1, wherein said encapsulation shell comprises lactic acid, poly(D,L-lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PLA), poly(e- caprolactone), poly(2-dimethylamino-ethylmethacrylate) homopolymer, poly(2- dimethylamino-ethylmethacrylate)-b-poly(ethyleneglycol)-a-methoxy-ro-metahcrylate copolymers, polycyanoacrylates or combinations thereof or PEGylated derivatives of any of the aforementioned.

9. The nanocapsule of claim 8, wherein said encapsulation shell comprises lactic acid, poly(D,L-lactic-co-glycolic acid) (PLGA) or combinations thereof.

10. The nanocapsule of any one of claims 7 to 9, wherein the oil formulation further comprises at least one surfactant.

11. The nanocapsule of any one of claims 7 to 9, wherein the oil formulation comprises octanoic acid and oleic acid.

12. The nanocapsule of claim 11 , wherein the ratio of octanoic acid to oleic acid is between about 1 :2 and 1:4 (wt/wt).

13. The nanocapsule of any one of claims 1 to 12, having an average diameter of between about 150 and 500 nm.

14. A method of preparing a nanocapsule of any one of claims 1 to 13, the method comprising:

mixing (i) an oil formulation comprising octreotide or a salt thereof, and octanoic acid with (ii) a solution of a hydrophobic polymer in a solvent, to thereby form an organic phase; and

adding water to said organic phase under conditions permitting formation of said nanocapsules.

15. The method of claim 14, wherein said oil formulation further comprises oleic acid.

16. The method of claim 15, wherein the ratio of octanoic acid to oleic acid is between about 1 :2 and 1:4 (wt/wt).

17. The method of any one of claims 14 to 16, wherein said oil formulation further comprises at least one surfactant.

18. The method of any one of claims 14 to 17, wherein said hydrophobic polymer comprises lactic acid, poly(D,L-lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PLA), poly(8-caprolactone), poly(2-dimethylamino-ethylmethacrylate) homopolymer, poly(2-dimethylamino-ethylmethacrylate)-b-poly(ethyleneglycol)-a-methoxy-ro- metahcrylate copolymers, polycyanoacrylates or combinations thereof.

19. The method of any one of claims 14 to 18, wherein said solvent is a nonaqueous solvent.

20. The method of any one of claims 14 to 18, wherein said solvent is ab organic solvent.

21. The method of claim 20, wherein the solvent is selected from acetone, ethanol and mixtures thereof.

22. A microparticle of at least one hydrophilic polymer, the microparticle comprising at least one nanocapsule comprising a core and a hydrophobic encapsulation shell, the core comprising octreotide or a salt thereof and octanoic acid, wherein said at least one nanocapsule is embedded in the hydrophilic polymeric matrix.

23. The microparticle of claim 22, comprising a plurality of said nanocapsules.

24. The microparticle of claim 22 or 23, wherein said hydrophilic polymeric matrix is in a solid or semi-solid form.

25. The microparticle of any one of claims 22 to 24, wherein said hydrophilic polymer is selected from poly(methacrylic acid), ethyl acrylate, polyols, polycarbohydrates, hydroxypropylmethyl cellulose (HPMC), hydroxymethyl cellulose, hydroxypropylmethylcellulose phthalate (HP55), cellulose acetate phthalate, carboxy- methylcellulose phthalate, copolymers and mixtures thereof.

26. The microparticle of any one of claims 22 to 25, wherein said matrix comprises an HPMC:Eudragit (poly(methacrylic acid)-ethyl acrylate copolymer) blend.

27. The microparticle of any one of claims 22 to 26, having an average diameter of between about 0.5 and 20 μπι.

28. A method of preparing a microparticle of any one of claims 22 to 27, the method comprising:

mixing (i) a suspension of nanocapsules with (ii) an aqueous solution of at least one hydrophilic polymer to obtained a mixed suspension; each of said nanocapsules comprising a core and a hydrophobic encapsulation shell, the core comprising octreotide or a salt thereof and octanoic acid; and micronizing said mixed suspension, thereby obtaining said microparticles.

29. The method of claim 28, wherein said at least one hydrophilic polymer is an HPMC:Eudragit (poly(methacrylic acid)-ethyl acrylate copolymer) blend.

30. The method of claim 29, wherein said aqueous solution has a pH of about 5.5- 6.5.

31. The method of any one of claims 28 to 30, wherein said solution is pH controlled by the addition of at least one buffer solution.

32. A method of preparing a microparticle comprising octreotide or a salt thereof, the process comprising:

mixing (i) an oil formulation comprising octreotide or a salt thereof, octanoic acid and oleic acid, with (ii) a solution of a hydrophobic polymer in a solvent, to thereby form an organic phase;

adding water to said organic phase under conditions permitting formation of a nanocapsules suspension, the nanocapsules comprising a core of said oil formulation and an encapsulation shell comprising said hydrophobic polymer; mixing said suspension of the nanocapsules with an aqueous solution of at least one hydrophilic polymer to obtained a mixed suspension; and micronizing the mixed suspension, thereby obtaining said microparticles.

33. A pharmaceutical composition comprising at least one microparticle of any one of claims 22 to 27 and at least one pharmaceutically acceptable carrier or excipient.

34. The pharmaceutical composition of claim 33 being in a form selected from a powder, a tablet, a capsule, a granule, a pill, a lozenge, a troche, a sachet, a chewing gum, and a suspension.

35. A microparticle of any one of claims 22 to 27 for use in oral delivery of octreotide or a salt thereof to a subject in need thereof.

36. Use of the microparticle of any one of claims 22 to 27 for the preparation of a medicament for oral delivery of octreotide or a salt thereof.

37. A method of administration of octreotide or a salt thereof to a person in need thereof, the method comprising orally administering to the subject a microparticle of any one of claims 22 to 27.

38. An oil formulation consisting of octreotide or a salt thereof and octanoic acid, optionally further comprising oleic acid.

39. The oil formulation of claim 38, consisting of octreotide or a salt thereof, octanoic acid, and oleic acid.

40. The formulation of claim 38 or 39, wherein said salt is selected from octreotide acetate, octreotide pamoate, octreotide diacetate, octreotide trifluoroacetate (TFA octreotide), and salts of octreotide and saturated fatty acids.

41. The formulation of claim 40, wherein said saturated fatty acid having a carbon chain length of Cs-i6.

42. The formulation of claim 40, wherein octreotide salt is octreotide acetate.

43. The formulation of any one of claims 38 to 42, comprising between about 5 and 125 mg/ml of octreotide or a salt thereof.