ES2363419T3 - FORMULATIONS OF SOMATOSTATINE ANALOGS. - Google Patents

Abstract

A pre-formulation, comprising a low viscosity mixture of: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog in which the ratio of a: b is in the range of 40:60 to 70:30; and in which the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure after coming into contact with an aqueous fluid.

Description

The present invention relates to precursors of formulations (pre-formulations) for the in situ generation of compositions for the controlled release of somatostatin analogs. In particular, the invention relates to pre-formulations of amphiphilic components and at least one somatostatin analog for parenteral application, which undergo a phase transition after exposure to aqueous fluids, such as body fluids, thus forming a controlled release matrix. .

Many bioactive agents that include pharmaceutical components, nutrients, vitamins, etc. They have a "functional window." That is, there is a range of concentrations over which these agents can be seen to provide some biological effect. When the concentration in the appropriate part of the body (for example, locally or as demonstrated by serum concentration) falls below a certain level, no beneficial effect can be attributed to the agent. Similarly, there is usually a higher level of concentration above which no additional benefit is derived from increasing the concentration. In some cases, increasing the concentration above a particular level results in undesirable or even dangerous effects.

Some bioactive agents have a prolonged biological half-life and / or a wide functional window and, therefore, can be occasionally administered, maintaining a functional biological concentration above a substantial period of time (e.g., 6 hours to several days) . In other cases, the disappearance rate is high and / or the functional window is narrow and, therefore, to maintain a biological concentration within this window, regular (or even continuous) doses of a small amount are necessary. This can be particularly difficult when non-oral routes of administration are not desirable (for example, parenteral administration), since self-administration can be difficult and, therefore, cause inconvenience and / or poor compliance. In these cases, it would be advantageous for a single administration to provide active agent at a therapeutic level throughout the entire period during which the activity is necessary.

WO 2005/046642 refers to the supply of peptides and proteins in pharmaceutical and nutritional compositions in lipid-based delivery systems and WO 2005/070394 refers to the supply of active agents in amphiphilic compositions and formulations. WO 97/13528 refers to pharmaceutical compositions for the administration of an active substance to or through the skin or mucosal surface, while WO 98/47487 refers to the supply of crystal-based bioadhesive drugs. liquids US 6464987 describes a fluid pharmaceutical composition that allows the controlled release of at least one active substance. US 5807573 refers to compositions containing a diacyl glycerol, a phospholipid and, optionally, a polar liquid that forms a liquid crystalline phase in which a biologically active material is dissolved or dispersed. US 5531925 and WO 93/06921 refer to particles comprising non-laminar liquid crystalline phases with applications such as drug delivery systems.

Somatostatin is a 14-residue cyclic peptide hormone that has the sequence Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys, in which the two cysteine residues they are connected by a disulfide bridge to generate a  type II turn in the key binding sequence of the Phe-Trp-Lys-Thr. Somatostatin is a natural peptide hormone also known as a growth hormone release inhibitor, and it has a function as an antagonist of insulin, glycogen and other certain hormones in the release of somatotrophin (human growth hormone). The biological half-life of natural somatostatin is very short (1-3 minutes) and therefore, by itself, is not a viable therapeutic component, but an increasing number of somatostatin analogues with superior activities and) or Longer disappearance times in vivo.

Somatostatin analogues, such as octreotide, lanreotide, vapreotide and related peptides, are used or indicated in the treatment of a variety of conditions in which they are normally administered over a prolonged period.

Octreotide, for example, is the synthetic octa-peptide with the sequence D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol (disulfide bridge 2-7) and is usually administered as the acetate salt Various clinical studies also characterize octreotide pamoate. This derivative retains the  key Phe- (D) Trp-Lys-Thr spin but, in contrast to the natural hormone, has a half-life ends of approximately 1.7 hours. Octreotide is used in the treatment of conditions that include carcinoid tumors and acromegaly, and after an initial dose it is normally provided over a sustained period of weeks or, more commonly, many months or years. In addition, somatostatin analogs are indicated in the treatment of many cancers, since a wide variety of tumors have been found to express somatostatin receptors. Of particular interest are those expressing the "sst (2)" and / or "sst (5)" receptor.

The most common "simple" formulation of octreotide is "Santostatin" (registered trademark) of Novartis. This is a solution for subcutaneous injection (s.c.) and a dose of 100 µg reaches a peak concentration of 5.2 ng / ml in 0.4 hours after injection. The duration of the action can be up to 12 hours, but the dosage s.c.

It usually takes place every 8 hours. Obviously, an injection s.c. 3 times a day for periods of months or years is not an ideal dosage regimen.

In order to avoid the need for multiple daily injections of octreotide, another formulation, "Santostatin LAR" (registered trademark) is available. This is an octreotide formulation in microspheres of poly (lactic-glycolic acid) that, after a new suspension, can be administered by intra-muscular injection (i.m.).

Carcinoid tumors are intestinal tumors that arise from specialized cells with paracrine functions (APUD cells). The primary tumor is commonly in the appendix, in which it is clinically benign. Secondary and metastatic intestinal carcinoid tumors secrete excessive amounts of vasoactive substances, including serotonin, bradykinin, histamine, prostaglandins and polypeptide hormones. The clinical outcome is carcinoid syndrome (an episodic skin redness syndrome, cyanosis, abdominal spasms and diarrhea in a patient with valvular heart disease and, less commonly, asthma and atrophy). These tumors can grow anywhere in the gastrointestinal tract (and in the lungs) with approximately 90% in the appendix. The rest occurs in the ileum, stomach, colon and rectum. Currently, the treatment of carcinoid syndrome begins with a bolus injection i.v. followed by infusion i.v. When a sufficient effect on the symptoms has been established, treatment is started with an octreotide reservoir formulation formulated in poly (lactic-co-glycolic acid) (PLGA) microspheres. However, during the first two weeks or more after the injection of the reservoir, s.c. injections are recommended. daily with octreotide to compensate for the slow release from the PLGA spheres.

Acromegaly is a rare chronic and insidious hormonal disorder that occurs when the pituitary gland produces excess growth hormone (GH). It most commonly affects middle-aged adults and can lead to premature death.

Diabetes mellitus, hypertension and increased risk of cardiovascular disease are the most serious health consequences of acromegaly. In addition, patients with acromegaly have an increased risk of developing colon polyps, which can be cancerous. The prevalence of acromegaly is approximately 60 cases per million population, and the incidence is 3.3 new cases per million per year. The term acromegaly comes from the Greek words for "limbs" (acro) and "large" (megalia), because one of the most common symptoms of this state is abnormal growth of the hands and feet.

Acromegaly is caused by prolonged overproduction of growth hormone (GH) and excessive production of insulin-like growth factor I (IGF-I). In 98 percent of cases, overproduction of GH is caused by a pituitary adenoma. The rate of GH production and the aggressiveness of the tumor vary from one patient to another. Generally, more aggressive tumors are seen in younger patients.

Acromegaly is a serious disease often diagnosed late. The morbidity and mortality rates are high, in particular, due to the associated cardiovascular, cerebrovascular and respiratory malignancies and disorders.

Acromegaly treatment is initiated by a period of injections s.c. three times a day (optimal daily dose = 300 µg octreotide). After the last dose s.c. and if a suitable effect is provided, a treatment is then started with an octreotide reservoir formulation formulated in poly / lactic-co-glycolic acid) (PLGA). Dose adjustments are made after biomarker measurement (HG and IGF-1), usually after approximately 3 months.

The existing octreotide slow release formulation is based on a well established type of depot formulation degrading polymer. Typically, these formulations are based on a biodegradable polymer such as poly (lactic acid) (PLA) and / or poly (lactic-co-glycolic acid) (PLGA) and may be in the form of a solution in an organic solvent, a pre -polymer mixed with an initiator, encapsulated polymer particles or (as in the case of octreotide), polymer microspheres.

The polymer or polymer particles trap the active agent and are gradually degraded, releasing the agent by slow diffusion and / or as the matrix is absorbed. Examples of these systems include those described in US 4938763, US5480656 and US6113943 and may result in the supply of active agents for a period of up to several months. However, these systems have a number of limitations that include manufacturing complexity and sterilization difficulty (especially microspheres). Local irritation caused by lactic and / or glycolic acid that is released at the injection site is also an appreciable inconvenience. There is also often a fairly complex procedure for preparing the injection dose from the powder precursor.

A highly significant drawback of the known PLGA octreotide deposition system is the complexity of preparation for the person in charge. The reservoir is provided in the form of a powder precursor of the microspheres containing octreotide, plus a diluent in which they must be uniformly suspended. Successful preparation of the delivery system for administration requires a multistage method that must be followed precisely in order to ensure that the powder precursor is fully saturated and in a uniform suspension before injection. The reservoir system should then be administered immediately by a method that includes tilting the syringe to maintain a uniform dispersion to the point of deep intramuscular injection in the buttock.

An additional limitation of octreotide deposition systems in PLGA is that the dosage cannot be easily adapted to suit particular patients. It has recently been proposed that the dosage of somatostatin analogs should be relative to the subject's body weight, since plasma concentrations have shown considerable variability with the subject's weight. However, a reservoir system comprising a previously heavy dry powder that is unstably suspended in an injection vehicle does not allow any such control, unless a considerable range of previously measured doses is provided. The suspension cannot be partially administered because the particles are not uniformly suspended. Therefore, it would be a considerable advantage to have a homogeneous deposit precursor that allows the administration of a dose to be decided on a specific basis of the subject at the time of administration.

From a drug supply point of view, polymer deposition compositions generally have the disadvantage of accepting only relatively low drug contents and having a "sharp increase / arrest" release profile. The nature of the polymer matrix, especially when applied as a solution or pre-polymer, causes an initial sharp increase in drug release when the composition is first administered. This is followed by a slow release period, while degradation of the matrix begins, finally followed by an increase in the release rate to the desired sustained profile. This sudden increase / arrest release profile may cause the in vivo concentration of active agent to a sharp increase above the functional window immediately after administration, then a further fall to the bottom of the functional window during the period of detention before reaching a sustained functional concentration. Obviously, from a functional and toxicological point of view, this profile of sharp increase / arrest is not desirable and could be dangerous. It can also limit the equilibrium concentration that can be provided, due to the danger of adverse effects at the "peak" point.

In the case of octreotide, the functional window varies in the range of about 0.8 to 20+ ng / ml. A recent clinical study indicates that higher values are effective in patients with carcinoid tumors of the midgut and high dose treatment may be an important addition to current therapeutic resources for patients with carcinoid tumors of the progressive and advanced gut: Welin et to the. (European Journal of Endocrinology 151 (2004) 107-112). Even so, as indicated above, the use of PLGA microspheres causes a detention of several weeks during which "recovery" injections should be provided. Obviously, it would be an advantage to provide a deposit system that achieves a "platform" level more quickly. The release of octreotide in rabbits from a PLGA microsphere product was studied by Comets et al. (J. Controlled Released 59 (1999) 197-05), for example, and this indicated that the "third phase" release of more than 85% of the active agent began more than 15 days after administration.

The low content loading capacity of polymeric deposit products, as well as the nature of the microparticles, causes additional administration problems. In particular, a relatively high volume of approximately 5 ml must be injected in order to carry the microparticle suspension, and the suspension can easily block the syringe needles (hence the need for adhesion for strict protocols of administration), thus requiring a relatively wide needle (for example, 19 gauge). These two factors, as well as the need for an i.m. injection deep, give rise to considerable discomfort for the patient during administration. It would be a considerable advantage that the deposit system could be provided with lower administration volumes, which are administrable through a narrower gauge needle and / or that does not require this deep injection.

The manufacture of PLGA microgranules is additionally a considerable difficulty with existing somatostatin analog deposit systems. In particular, since the granules are particles, they cannot be filtered under sterile conditions and, in addition, as the PLGA copolymer melts at approximately 40 ° C, they cannot be heat treated for sterility. As a consequence, a manufacturing process of the complex must be performed under conditions of high sterility.

The present inventors have now established that by providing a prior formulation comprising certain amphiphilic components, at least one somatostatin analogue and a biologically tolerable solvent in a low viscosity phase, such as a molecular solution, a pre-formulation can be generated by addressing many of the deficiencies of the deposit formulations of previous somatostatin analogues. In particular, the preformulation is easy to manufacture, can be filtered under sterile conditions, has a low viscosity (allowing easy and less painful administration, usually by means of a narrow needle), allows a high level of bioactive agent to be incorporated ( thus allowing a smaller amount of composition to be used), requires a more superficial injection and) or forms a desired non-laminar deposit composition in vivo having a controllable "abrupt" or "non-stop" release profile. The pre-formulation shows excellent storage stability and in vivo crucial for long acting products. The compositions are also formed from materials that are non-toxic, biotolerable and biodegradable.

In a first aspect, the present invention therefore provides a pre-formulation comprising a mixture

Low viscosity of: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog in which the ratio of a: b is in the range of 40:60 to 70:30; in which the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure after entering

in contact with an aqueous fluid. Generally, the aqueous fluid will be a body fluid, particularly an extra-vascular fluid, a fluid extracellular / interstitial fluid or plasma and the pre-formulation will form a liquid crystalline phase structure when

come into contact with this fluid (for example, in vivo). The pre-formulation of the invention generally does not It will contain no significant amount of water before administration. In a second aspect of the invention, there is also provided a method of supplying an analogue of

somatostatin to the body of a human being or a non-human animal (preferably mammalian), this method comprising administering parenterally (for example, i.m. or preferably s.c.) a pre-formulation comprising a low viscosity mixture of:

a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog; in which the ratio of a: b is in the range of 40:60 to 70:30; so that at least one liquid crystalline phase structure is formed after coming into contact with a fluid

aqueous in vivo following administration. Preferably, the pre-formulation administered in this

method is a pre-formulation of the invention, as described herein. In a third aspect of the invention, there is also provided a method for the local delivery of a somatostatin analog to the body of a human being or a non-human animal (preferably mammalian), this method comprising administration proximal to the disease zone ( for example, an intravitreal supply for the treatment of a diabetic retinopathy in which systemic effects are not desired) of a pre-formulation comprising a low viscosity mixture of:

a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog in which the ratio of a: b is in the range of 40:60 to 70:30; so that at least one liquid crystalline phase structure is formed after coming into contact with a fluid

aqueous in vivo following administration. Preferably, the pre-formulation administered in this

Method is a pre-formulation of the invention as described herein. In a further aspect, the present invention also provides a method for the preparation of a liquid crystalline reservoir composition comprising exposing a pre-formulation comprising a mixture Low viscosity of:

a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog; in which the ratio of a: b is in the range of 40:60 to 70:30; to at least one aqueous fluid in vivo.

Preferably, the pre-formulation administered is a pre-formulation of the present invention as described.

in the present specification. Still, in a further aspect, the present invention provides the formation of a suitable pre-formulation for the administration of a bioactive agent to a subject (preferably a mammal), said comprising procedure form a low viscosity mixture of

a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; in which the ratio of a: b is in the range of 40:60 to 70:30; and dissolve or disperse the 0.1-10% p dispersion of at least one somatostatin analog in the low mixture

viscosity, or at least one of the components a, g or c, before forming the low viscosity mixture. Preferably, the pre-formulation thus formed is a formulation of the invention as described herein.

Still, even in a further aspect, the present invention provides the use of a low viscosity mixture. from: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog;

in which the ratio of a: b is in the range of 40:60 to 70:30; in the manufacture of a pre-formulation for use in the sustained administration of said analog of somatostatin, wherein said pre-formulation is capable of forming at least one liquid crystalline phase structure after being contacted with an aqueous fluid.

Still in a further aspect, the present invention provides a method for the treatment of a human or non-human mammal that needs it with a somatostatin analog, said method comprising administering to said subject a pre-formulation comprising a low viscosity mixture of :

a) at least one diacyl glycerol; b) at least one phosphatidyl choline; d) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog; in which the ratio of a: b is in the range of 40:60 to 70:30. Preferably, the treatment method is a method for the treatment of at least one selected state.

between acromegaly, cancers (such as carcinomas and melanomas, tumors that express at least one somatostatin receptor, sst (2) -positive tumors, sst (5) -positive tumors, prostate cancers, astro-whole-pancreatic neuroendocrine tumors (GEP NE ) and especially carcinoid tumors, insulinomas, gastrinomas, vasoactive intestinal peptide tumors (VIP) and glucagonomas), elevated growth hormone (GH), elevated insulin-like growth factor (IGF-I), variceal hemorrhage (especially esophageal) , gastrointestinal problems induced by chemotherapy (such as diarrhea), lymphorerrhea, diabetic retinopathy, thyroid eye disease, obesity, pancreatitis and related conditions.

Still, in another aspect, the present invention provides the use of: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog; in which the ratio of a: b is in the range of 40:60 to 70:30; in the manufacture of a low viscosity pre-formulation medicament for use in in vivo formation

of a deposit for the treatment of acromegaly, cancer (such as carcinomas and melanomas, tumors that express

at least one somatostatin receptor, sst (2) -positive tumors, sst (5) -positive tumors, prostate cancers, gastro-whole-pancreatic neuronedocrine tumors (GEP NE) and especially carcinoid tumors, insulinomas, gastrinomas, peptide tumors vasoactive bowel (VPI)), high growth hormone (GH), high insulin growth factor I (IGF-I), variceal bleeding (especially esophageal), gastrointestinal problems induced by chemotherapy (such as diarrhea), lymphorea, diabetic retinopathy , thyroid eye disease, obesity, pancreatitis and / or related conditions.

The pre-formulations of the present invention are highly advantageous in that they are stable in an extended storage in its final "ready for administration" form. As a consequence, they can be easily provided for administration by healthcare professionals or by patients or their caregivers, who do not need to be fully trained healthcare professionals and may not have the experience or skills to produce complex preparations.

Still, in a further aspect, the present invention provides a disposable delivery device (which must also include a device component) previously loaded with a measured dose of a preformulation of the present invention. This device will normally contain a single dose prepared for administration and will generally be packaged under sterile conditions so that the composition is stored within the device until administration. Suitable devices include cartridges, ampoules and, in particular, syringes and syringe cylinders, with integral needles or with standard settings (eg, luer) adapted to accept a suitable disposable needle.

The previously filled devices of the invention can also be suitably included in an administration kit, a case that also forms a further aspect of the invention. In yet another aspect, the invention thus provides a kit for the administration of at least one somatostatin analog, said kit containing a measured dose of a formulation of the invention and, optionally, an administration device or component therefor. Preferably, the dose will be maintained within the device or component, which will be suitable for an i.m. administration. or, preferably, s.c. The cases may include additional administration components such as needles, caps, etc. and will optionally and preferably contain instructions for administration. These instructions will normally refer to administration by a route as described herein and / or for the treatment of a disease indicated above in this specification.

The formulations of the present invention generate a non-laminar liquid crystalline phase following administration. The use of non-lamellar phase structures (such as liquid crystalline phases) in the supply of bioactive agents is relatively well established today. These structures are formed when an amphiphilic compound is exposed to a solvent because the amphiphile has both polar and apolar groups that group together to form polar and apolar zones. These zones can efficiently solubilize both plantar and apoplate compounds. In addition, many of the structures formed by amphiphiles in polar and / or apolar solvents have a very considerable area of polar / apolar contour in which other amphiphilic compounds can be adsorbed and stabilized. Amphiphiles can also be formulated to protect other active agents, at least to some extent, from aggressive biological environments, including enzymes, and thus provide advantageous control over the stability and release of other active agents.

The formation of non-laminar zones in the phase diagrams of amphiphile / water, amphiphile / oil and amphiphile / oil / water is a well known phenomenon. These phases include liquid crystalline phases such as the cubic P, cubic D, cubic G and hexagonal phases, which are fluid at the molecular level but show a significant order of wide range and the L3 phase comprising a continuously interconnected multiple lattice of bilayer sheets that are not laminar but lack the order of wide range of liquid crystalline phases. Depending on their curvature of the amphiphilic sheets, these phases can be described as normal (medium curvature towards the apolar zone) or inverted (average curvature towards the polar zone).

The liquid crystalline phases and non-laminar L3 are thermodynamically stable systems. That is, they are not simply a meta-stable state that will separate and / or reform in the form of layers, lamellar phases or the like, but they are the thermodynamically stable form of the lipid / solvent mixture.

It is important that the pre-formulations of the invention are not liquid crystalline before administration because the liquid crystalline phase in its volume is generally highly viscous. The pre-formulations, therefore, are non-liquid crystalline formulations of low viscosity, which undergo a phase change after administration to form a liquid crystalline mass. Particularly preferred examples of low viscosity mixtures are molecular solutions and / or isotropic phases such as phases L2 and / or L3. As described above, Phase Le is a non-laminar interconnected sheet that has some phase structure but lacks the wide range order of a liquid crystalline phase. Unlike the liquid crystalline phases, which are generally highly viscous, the L3 phases are of a lower viscosity. Obviously, mixtures of L3 phase and molecular solution and / or Le phase particles suspended in a volume molecular solution of one or more components are also suitable. The L2 phase is the so-called "inverted micellar" or microemulsion phase. The most preferred low viscosity mixtures are molecular solutions, L3 phases and mixtures thereof. L2 phases are less preferred, except in the case of swollen L2 phases, as described below.

As used herein, the term "low viscosity mixture" is used to indicate a mixture that can be easily administered to a subject and, in particular, easily administered by means of a standard syringe and needle arrangement. This may be indicated, for example, by the ability to be supplied from a 1 ml disposable syringe through a small gauge needle. Preferably, the low viscosity blends can be supplied through a 19 awg gauge needle, preferably a smaller needle than the 19 gauge, more preferably 23 awg (or most preferably even 27 gauge) by manual pressure. In a particularly preferred embodiment, the low viscosity mixture should be a mixture capable of passing through a standard sterilized filtration membrane such as a 0.22 µm syringe filter. A typical range of suitable viscosities would be, for example, 0.1 to 5000 mPas, preferably 1 to 1000 mPas at 20 ° C.

It has been observed that by adding small amounts of low viscosity solvent, as indicated herein, a very significant change in viscosity can be provided. As indicated in Figure 1, for example, the addition of only 5% solvent to a lipid mixture can reduce the viscosity 100 times and the addition of 10% can reduce the viscosity up to 10,000 times. In order to achieve this non-linear synergistic effect of lowering viscosity, it is important that a solvent of appropriately low viscosity and adequate polarity be employed. These solvents include those described later in the present specification.

The present invention provides a pre-formulation comprising components a, b, c and at least one somatostatin analog, as indicated herein. The amounts of these components will normally be in the range of 40-70% of a), 30-60% of b) and 0.1-10% of c), with the somatostatin analog present at 0.1% up to 10 %. All% are by weight throughout the specification, unless otherwise indicated. The formulations may consist essentially only of these components and, in one aspect, consist entirely of these components. Preferably, the ranges for component a) are 43-60%, particularly 45-55 and the preferable ranges for component b) are 35-55%, particularly 40 to 50%.

The ratios of a: b are normally 40:60 to 70:30, preferably 45:55 to 60:40 and, more preferably,

48:52 to 55:45. The approximately 50:50 ratios are highly effective.

The amount of solvent component c) in the pre-formulation will have a considerable effect on several characteristics. In particular, the viscosity and speed (and duration) of the release will be significantly altered with the level of solvent. The amount of solvent, therefore, will be at least sufficient to provide a low viscosity mixture, but additionally it will be determined in order to provide the desired release rate. This can be determined by routine methods considering the following examples. Normally, a level of 0.1 to 10% solvent will provide adequate release properties and viscosity. This will preferably be from 2 to 8% and an amount of approximately 5% is highly effective.

The remarkable discovery of the present inventors is that the proportion of solvent in the formulation can be used to "fine tune" the release profile of the active agent during the first few days of release. In particular, although all the formulations of the invention have a surprisingly low "rise / stop" effect (in fact, there may be no detention period at all) and reach a platform release level in a few days (for example, 5 days, preferably 3 days, more preferably 1 day) of injection, if a controlled "sudden increase" / initial release of active agent is required in the first 1-2 days, then this can be provided by increasing the proportion of solvent to the upper zone of the interval provided above. On the contrary, in the middle to lower range of the range, a formulation is provided that provides a deposit essentially without sharp increase and rapid fall to the platform release level.

Thus, in one embodiment, the present invention provides formulations and deposits containing approximately 0.1 to 6% p of component c) and having a low release of the active compound during the first days after administration ("profile without increase abrupt"). In an alternative embodiment, the present invention provides formulations and deposits that contain approximately 6.5 to 10% of component c) and that have a high initial release of the active compound during the first days after administration ("sharp increase profile" ).

The low initial release (“profile without sharp increase”) of active agent is defined so that the area under a plasma concentration versus the time of the curve during the first 24 hours is less than 15% of the area under the curve for the complete curve (measured or extrapolated from time 0 to infinity or from time 0 to the time value of sampling), more preferably less than 10% and most preferably less than 7%. In addition, the fall to the plasma concentration levels of the platform after the initial peak should be rapid, so that the platform is reached in 48 hours, more preferably in 24 hours and most preferably in 12 hours. Conversely, a high initial release ("sharp increase profile") is such that more than 15% of active agent is released within 24 hours and more preferably, more than 20% is released during the first 24 hours. The fall to the platform will not occur until after 36 hours, more preferably after 48 hours and most preferably after 72 hours. It is preferable that each of these profiles be combined with a rapid settlement of the active agent concentration to the "platform" level. For example, the plasma concentration after 10 days should be no more than 50% greater or less than the average concentration on days 5 to 20. Preferably, it will be no more than 30% and, more preferably, no more than twenty%.

As indicated above, the amount of component c in the pre-formulations of the invention will be at least sufficient to provide a mixture of low viscosity (eg, a molecular solution, see above) of components a, b and c will be readily determined. for any particular combination of components by standard methods. The phase behavior itself can be analyzed by techniques such as visual observation in combination with polarized light microscopy, nuclear magnetic resonance and cryo-transmission electron microscopy (cryo-TEM) to look for solutions, L2 or L3 phases or liquid crystalline phases. The viscosity can be measured directly by standard means. As described above, an appropriate practical viscosity is that which can be effectively handled in syringes and particularly filtered under sterile conditions. This will be easily assessed as indicated herein.

The "a" component as indicated herein is at least one diacyl glycerol (DAG) and therefore has two non-polar "tail" groups. The two non-polar groups may have an equal or different number of carbon atoms and can be independently saturated or unsaturated. Examples of non-polar groups include C6-C32 alkyl and alkenyl groups, which are normally present as the long chain carboxylic acid esters. These are often described by reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Therefore, CX: Z indicates a hydrocarbon chain having X carbon atoms and X unsaturations. Particular examples include the groups capropyl (C6: 0), cariloyl (C8: 0), capryl (C10: 0), lauroyl (C12: 0), myristoyl (C14: 0), palmitoyl (C16: 0), phyanoñyl (C16 : 0), palmitoleoyl (C16: 1), stearoyl (C18: 0), oleoyl (C18: 1), elaidoyl (C18: 1), linoleoyl (C18: 2), linolenoyl (C18: 3), arachidonoyl (C20: 4), behenoyl (C22: 0) and lignocerolyl (C24: 9 :). Therefore, typical non-polar chains are based on lipid fatty acids from natural esters, which include caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic acids, arachidonic, behenic or lignoceric, or the corresponding alcohols. Preferred non-polar chains with palmitic, stearic, oleic and linoleic acids, particularly oleic acid.

Mixtures of any number of diacil lipids can be used as component a. Preferably, this component will include at least a portion of glycerol dioleate (GDO). A highly preferred example is DAG comprising at least 50%, preferably at least 80% and even comprising substantially 100% GDO.

Since GDO and other diacyl glycerols are products derived from natural sources, there is generally a certain proportion of "contaminant" lipid that has other chain lengths, etc. In one aspect, the GDO as used in the present invention is used both to indicate any commercial quality of GDO with accompanying impurities (ie, commercial purity GDO). These impurities can be separated and removed by purification, but it is rarely necessary to provide the quality that is congruent. However, if necessary, the "GDO" may be GDO essentially of chemical purity, such as at least 80% pure, preferably at least 85% pure and, more preferably, GDO at least 90% pure.

Component "b" in the present invention is at least one phosphatidyl choline (PC). As with component a, this component comprises a polar head group and at least one non-polar tail group. The difference between the components a and g is mainly based on the polar group. The non-polar parts, therefore, can be suitably derived from the fatty acids or corresponding alcohols previously considered for component a. As with component a), the PC will contain two non-polar groups.

The phosphatidyl choline part, even more suitably than any part of diacyl glycerol, can be derived from a natural source. Suitable sources of phospholipids include egg, heart (e.g., bovine (, brain, liver (e.g., bovine)) and plant sources that include soy. These sources may provide one

or more constituents of component b, which may comprise any mixture of phospholipids. Any single PC or a mixture of PCs from these or other sources can be used, but mixtures comprising soy PC or egg PC are highly suitable. PC with at least 50% soybean PC, more preferably at least 75% soybean PC and, most preferably, essentially pure soybean PC is preferred, although the mixtures of soybean and egg PCs for the same proportions are also highly effective.

Since the pre-formulations of the invention are to be administered to a subject for the controlled release of an active somatostatin analog agent, it is important that the components be biocompatible. In this regard, the pre-formulations of the present invention are highly advantageous since both PC and DAG are well tolerated and decompose in vivo into components that are naturally present in the body of a mammal.

A particularly favorable combination of components a and b are GDO with PC, especially GDO with soy PC and / or egg PC.

Component "c" of the pre-formulations of the invention is an organic solvent containing oxygen. Since the pre-formulation will generate a depot composition after administration (for example, in vivo), after coming into contact with an aqueous fluid, it is desirable that this solvent is tolerable by the subject and is capable of mixing with the aqueous fluid and / or to diffuse or dissolve the pre-formulation in the aqueous fluid. Therefore, solvents having at least moderate water solubility are preferred.

In a preferred version, the solvent is such that a relatively small addition to the composition comprising a and b, that is, preferably below 10%, provides ample viscosity reductions of an order of magnitude or more. As described herein, the addition of 10% solvent can provide a reduction of two, three or even four orders of magnitude in viscosity over the solvent-free composition, even if that composition is a solution or L2 phase. It contains no solvent, or an inappropriate solvent such as water or glycerol.

Typical solvents suitable for use as component c include at least one solvent selected from alcohols, ketones, esters (including lactones), ethers, amides and sulfoxides. The alcohols are particularly suitable and form the preferred class of solvents. Examples of suitable alcohols include ethanol, isorporpanol and glycerol-formal. Ethanol is the most preferred. Monols are preferred respectively to diols and polyols. When diols or polyols are used, this is preferably done in combination with at least an equal amount of monool or other preferred solvent. Examples of ketones include acetone, n-methyl-pyrrolidone (NMP), 2-pyrrolidone and propylene carbonate. Suitable ethers include diethyl ether, glycolurol, diethylene glycol, monoethyl ether, dimethyl isobarbide and polyethylene glycols. Suitable esters include ethyl acetate and isopropyl acetate and dimethyl sulfide is a suitable sulfide solvent. Suitable amides and sulfoxides include dimethylacetamide (DMA) and dimethylsulfoxide (DMSO), respectively.

A highly preferred combination is soy PC, GDO and ethanol.

It is preferable that little or nothing of component c contains halogen substituted hydrocarbons, since these have a lower biocompatibility. When a part of halogenated solvent, such as dichloromethane, is necessary, this proportion will generally be minimized.

Component c, as used herein, may be a single solvent or a mixture of suitable solvents, but will generally be of low viscosity. This is important because one of the key aspects of the present invention is that it provides pre-formulations that are of low viscosity and a major function of a suitable solvent is to reduce this viscosity. This reduction will be a combination of the effect of the lower viscosity of the solvent and the effect of the interactions between the solvent and the lipid composition. An observation of the present inventors is that the solvents containing low viscosity oxygen described herein have highly advantageous and unexpected molecular interactions with the lipid parts of the composition, thus providing a non-linear reduction of viscosity with the addition of A small volume of solvent.

The viscosity of the "low viscosity" solvent component c (single solvent or mixture) should normally be no more than 18 mPas at 20 ° C. This is preferably no more than 15 mPas, more preferably no more than 10 mPas and, most preferably, no more than 7 mPas at 20 ° C.

An additional advantage of the present pre-formulations is that a higher level of bioactive agent can be incorporated into the system. In particular, by the appropriate choice of components a-c (especially c), high levels of active agent can be dissolved or suspended in the pre-formulations. This allows a reduction in the volume administered and, therefore, less discomfort to the subjects.

The pre-formulations of the present invention usually do not contain significant amounts of water. As it is essentially impossible to separate each residual amount of water from a lipid composition, this should be considered as an indication that there is only this minimum residual amount of water that cannot be easily separated. This amount will generally be less than 1% by weight, preferably less than 0.5% by weight of the pre-formulation. In a preferred aspect, the pre-formulations of the invention do not contain glycerol, ethylene glycol or propylene glycol and contain no more than a residual amount of water, as just described.

The pre-formulations of the present invention contain one or more somatostatin analogs (which are provided by any reverence for "active agents" herein). Since somatostatin is a peptide hormone, typical somatostatin analogs will be peptides, especially 14 or less amino acids. Preferably, these peptides will be structurally restricted such as by being cyclic and / or having at least one intra-molecular cross-linking. Cross-links of amide, ester or particularly disulfide are highly suitable. Preferred restricted peptides will exhibit a  spin of type 2. This spin is present in the key area of somatostatin. The peptides may contain only amino acids selected from the 20 aminoácidos-amino acids indicated in the genetic code or, more preferably, may contain their isomers and other natural or non-natural amino acids (generally amino acids ,  or ) and their analogues and derivatives.

The terms and expressions "somatostatin analogs", "octreotide", "lanreotide" and other active agents cited herein clearly include their pharmaceutically acceptable salts and derivatives. normally, for example, the "octreotide" cited herein will be the most common salt, octreotide acetate, but the free molecule, or any other biologically acceptable salt, such as hydrochloride, pamoate, citrate, etc. It is also encompassed by the terms, unless the context excludes it.

The amino acid derivatives are especially useful in the terminations of the peptides, in which the amino or carboxylate terminal group may be substituted with any other functional group such as hydroxy, alkoxy, carboxy, ester, amido, thio, amino, alkylamino, di- or tri-alkylamino, alkyl (by which it is meant herein C1-C12 alkyl, preferably C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-sec - or t-butyl, etc.), aryl (for example, phenyl, benzyl, naphthyl, etc.) or other functional groups, preferably with at least one heteroatom and preferably having no more than 10 carbon atoms in total, preferably no more than 6.

Particularly preferred somatostatin analogs are restricted peptides of 6 to 10 alpha-amino acids, of which particular examples include octreotide, lanreotide (NH2- (D) Naph-Cys-Tyr- (D) Trp-Lyx-ValCys-Thr sequence -CONH2 and its cyclic derivative of sequence NH2- (D) -Naph-Cys-Tyr- (D) Phe-Lys-Val-Cys-Thr-CONH2 which both have a cross-linking of intramolecular disulfide Cys-Cys) and vapreotide. The most preferred is octreotide.

The somatostatin analog will generally be formulated as 0.1 to 10% by weight of the total formulation. Normal values will be 1 to 8%, preferably 2 to 6% and, more preferably, 2.5 to 5%. Somatostatin analog content of about 3% is most preferred.

The doses of somatostatin analogue suitable for inclusion in the formulation and, therefore, the volume of the formulation used will depend on the rate of release (controlled, for example, by the type of solvent and use of quantity) and the duration of the release, as well as the desired therapeutic level, the activity and the rate of disappearance of the particular active component chosen. Normally, an amount of 1 to 1000 mg (for example, 1 to 500 mg) per dose will be suitable to provide a therapeutic level between 7 and 180 (for example, between 7 and 90 days). This will preferably be 5 to 300 mg. For octreotide, the level will normally be approximately approximately the level will normally be approximately 10 to 180 mg (for example, 30 to 90 days in duration). Preferably, the amount of octreotide will be about 0.2 to 3 mg per day between injections. Therefore, a deposit administered every 30 days will have 6 to 90 mg or a 90 day deposit will have 18 to 270 mg octreotide. In some situations, especially when advanced tumors are present, a high dose equivalent to approximately 40 to 160 mg of octreotide per week duration (for example, 160 to 640 mg for a 4-week deposit will be appropriate. These deposits will normally be formulated for one administration once every 2-8 weeks, preferably once every 4-6 weeks.

The pre-formulations of the present invention are formulated to be administered parenterally. This administration will not generally be an intra-vascular method but will preferably be subcutaneous, intraocular (for example, intra-vitreal or subconjunctival) or intramuscular. Normally, administration will be by injection, a term used herein to indicate any method in which the formulation is passed through the skin, such as by needle, catheter or needleless injector.

The preferred parenteral administration is by i.m. injection. or s.c., most preferably by injection

s.c. deep This has the advantage of being less deep and less painful for the subject than the i.m. injection. (deep) used for current octreotide deposits and is technically the most appropriate in the present case as it combines ease of injection with a low risk of side effects to the skin.

The pre-formulations of the present invention provide non-lamellar liquid crystalline deposit compositions upon exposure to aqueous fluids, especially in vivo. As used herein, the term "non-laminar" is used to indicate a normal or inverted liquid crystalline phase (such as a cubic or hexagonal phase) or the L3 phase or any combination of the same. The term "liquid crystalline" indicates all hexagonal liquid crystalline phases and all cubic and / or all mixtures thereof. Hexagonal, as used herein, indicates "normal" or "inverted" (preferably inverted) and "cubic" hexagonal indicates any cubic liquid crystalline phase unless otherwise specified.

For many combinations of lipids, there are only certain non-laminar phases, or they exist in any stable state. It is a surprising feature of the present invention that the compositions described herein frequently exhibit non-lamellar phases that are not present with many other combinations of components. In a particularly advantageous embodiment, therefore, the present invention relates to compositions having a combination of components for which there is a phase zone I2 and / or L2 when diluted with an aqueous solvent. The presence or absence of these zones can easily be tested for any particular combination by simple dilution of the composition with an aqueous solvent and the study of the resulting phase structures by the methods described herein.

In a highly advantageous embodiment, the compositions of the invention can form a phase I2, or a mixed phase that includes phase I2 after being contacted with water. Phase I2 is an inverted cubic liquid crystalline phase that has discontinuous aqueous zones. This phase is particularly advantageous in the controlled release of active agents and, especially, in combination with polar active agents, such as water soluble active agents, because the discontinuous polar domains prevent the rapid diffusion of the active components. Deposit precursors in L2 are highly effective in combination with a phase I2 deposit formation. This is because the L2 phase is a phase called "inverted micellar" that has a continuous hydrophobic zone surrounding discrete polar nuclei. Therefore, L2 has similar advantages to hydrophilic active components. In transient phases after contact with a body fluid, the composition may comprise multiple phases, since the formation of an initial surface phase will delay the passage of solvent towards the core of the reservoir, especially with substantial sized administrations of internal reservoirs. Although theoretical linkages are not desired, it is believed that this transient formation of a surface phase, especially a surface liquid crystalline phase, serves to greatly reduce the "sharp increase / arrest" profile of the present compositions by immediately restricting the exchange rate between Composition and contours. The transitional phases may include (generally in order from the outside towards the center of the tank): HII or L, I2, L2 and liquid (solution). It is highly preferred that the composition of the invention be capable of forming at least two and, more preferably, at least three of these phases simultaneously in transient phases after coming into contact with water at physiological temperatures. In particular, it is highly preferred that one of the phases formed, at least temporarily, be phase I2.

It is important to appreciate that the pre-formulations of the present invention are of low viscosity. As a consequence, these pre-formulations should not be in any liquid crystalline phase by volume since all liquid crystalline phases have a significantly higher viscosity than could be administered by a syringe or spray supplier. The pre-formulations of the present invention will therefore be in a non-liquid crystalline state, as in the form of a solution, phase L2 or L3, particularly solution or L2. The L2 phase, as used throughout the present specification, is preferably a "swollen" L2 phase containing more than 10% by weight of solvent (component c) that has a viscosity reduction effect. This is in contrast to a "concentrated" or "non-swollen" L2 phase that does not contain solvent, or a smaller amount of solvent, or that contains a solvent (or mixture) that does not provide the decrease in viscosity associated with the solvents of low viscosity containing oxygen specified herein.

Upon administration, the pre-formulations of the present invention undergo a phase structure transition from a low viscosity mixture to a high viscosity deposit composition (generally tissue adherent). Generally, this will be a transition from a molecular mixture, swollen L2 and / or L3 phases to one or more liquid crystalline phases (high viscosity) such as inverted hexagonal or cubic liquid crystalline phases or mixtures thereof. As indicated above, additional phase transitions may also take place following administration. Obviously, the complete phase transition is not necessary for the operation of the invention, but at least one surface layer of the administered mixture will form a liquid crystalline structure. Generally, this transition will be rapid for at least the surface area of the administered formulation (which starts in direct contact with air, body surfaces and / or body fluids). This will most preferably be for a few seconds or minutes (for example, up to 30 minutes, preferably up to 10 minutes, more preferably 5 minutes or less). The rest of the composition can change the phases to a liquid crystalline phase more slowly by diffusion and / or as the surface area disperses.

In a preferred embodiment, therefore, the present invention provides a pre-formulation as described herein, of which at least one part forms a hexagonal liquid crystalline phase after coming into contact with an aqueous fluid. The hexagonal phase thus formed can generally be dispersed and / or degraded gradually, releasing the active agent, or it can subsequently become a cubic crystalline phase, which in turn then gradually disperses. It is believed that the hexagonal phase will provide a faster release of active agent, in particular of the hydrophilic active agent, than the cubic phase structure, especially phase I2 and L2. Therefore, when the hexagonal phase is formed before the cubic phase, this will result in an initial release of active agent to bring the concentration to an effective level quickly, followed by a gradual release of a "maintenance dose" as the cubic phase degrades. In this way, the release profile can be controlled.

Without subjecting to theoretical linkages, it is believed that upon exposure (for example, to body fluids), the preforms of the invention lose some or all of the organic solvent included therein (for example, by diffusion) and absorb aqueous fluid from the body environment (for example, the in vivo environment) so that at least a part of the formulation generates a particularly liquid non-laminar crystalline phase structure. In most cases, these non-laminar structures are highly viscous and do not dissolve or disperse easily in the environment in vivo. The result is that a monolithic "reservoir" is generated in vivo with only a limited area of exposure to body fluids. In addition, since the non-laminar structure has large polar, apolar and contour areas, it is highly effective in solubilizing and stabilizing active agents such as peptides and protecting them from degradation mechanisms. As the deposit composition formed from the preformulation gradually degrades over a period of days, weeks or months, the active agent is gradually released and / or diffused from the composition. Since the environment in the reservoir composition is relatively protected, the pre-formulations of the invention are highly suitable for active agents with a relatively low biological half-life (see above).

The deposit systems formed by the formulations of the present invention are highly effective in protecting the active agent from degradation and, therefore, allow a prolonged release period. Comparative tests have been carried out between the known PLGA slow release product and formulations of the present invention containing GDO, soybean PC, ethanol and octreotide. These indicate that the formulations of the present invention provide less degradation under simulated in vivo conditions than known octreotide compositions with PLGA microspheres. The formulations of the invention can therefore provide in vivo deposits of somatostatin analogues that require administration only once every 20 or 90 days, preferably 30 to 60 days, more preferably 35 to 48 days. Obviously, a longer stable release period is desirable for patient comfort and compliance, as well as a less demanding time for healthcare professionals.

A considerable advantage of the deposit precursors of the present invention is that they are stable homogeneous phases. That is, they can be stored for considerable periods (preferably at least 6 months) without phase separation. In addition to providing advantageous storage, this allows the dose of somatostatin analog to be selected with reference to the species, age, sex, weight and / or physical condition of the individual subject, by injecting a selected volume.

In addition, the present inventors have surprisingly found that the initial release of active agent (observed as Cmax) is not proportional to the volume of the dose, at intervals of at least 10 times in the injection of the sample volume (see examples and later figures), while the total drug exposure (observed as AUC or mean plasma platform concentration) is proportional to the injection volume. On the contrary, it has been shown that Cmax can be correlated with the surface area of the injected dose volume. That is, Cmax is proportional to two thirds of the power of the injected dose volume. Increasing the volume of the dose by a factor of 10 will not increase the Cmax 10 times and the relationship between Cmax and the total drug exposure (AUC or level of concentration of the average plasma platform) will therefore decrease with the increasing dose volume . This is highly advantageous, because this property reduces the risk of reaching potentially toxic plasma drug concentrations, even if the total dose is significantly increased. It also allows an independent degree of control over the platform concentration and peak concentration by varying the concentration of active component in the formulation and the volume injected. Even in situations where the dosage is not directly proportional to the injection volume, however, the homogeneous nature of the deposit precursors significantly allows a partial administration of a previously measured dose and this administration can be done by reference to a table, graph, program, calculation, etc. of dosage, which can take into account any or all of the relevant variables of the subject.

Therefore, the present invention provides methods comprising the selection of a specific dosage amount for an individual, particularly by body weight or body surface area. The means for this dose selection are by volume of administration.

It is an unexpected discovery of the present inventors that the pre-formulations give rise to a depot composition that has very little "sharp increase" effect on the active agent release profile. This is unexpected because it can be expected that the low viscosity mixture (especially if this is a solution) of the pre-composition would rapidly lose active agent after being exposed to water. In fact, the preforms of the invention have shown considerably less initial "sharp increase" than previously known polymer-based depot compositions, which tended to have an initial "rinse" of active surface-binding agent. This is illustrated in the subsequent examples and the figures associated therewith. In one embodiment, therefore, the invention provides injectable pre-formulations and resulting depot compositions in which the highest plasma concentration of active component after administration is no more than 10 times the average concentration between 24 hours and 5 days of administration. The ratio is preferably no more than 8 times and most preferably no more than 5 times the average concentration.

The compositions of the invention also allow the generation of depot compositions with very little "stop" effect after administration. In a further embodiment, therefore, the invention provides injectable pre-formulations and resulting depot compositions in which the plasma concentration of active component at 7 days after a single administration is not less than the plasma concentration of active component. at 21 days after administration. Similarly, the concentration of active component must be higher at all time values in the first 21 days than the concentration at any time from 30 days after administration onwards. This gradual decrease release profile has not been previously demonstrated for a somatostatin analog formulation.

An additional and considerable advantage of the deposition compositions formed by the pre-formulations of the present invention over the PLGA-based deposits is that the compositions of the invention produce fewer lesions at the injection site. PLGA is a biodegradable polymer that generates lactic and glycolic acids after decomposition and therefore releases these irritating by-products during the entire active agent release period (and potentially longer). This results in the formation of a "capsule" and the generation of scar tissue that can remain for prolonged periods after administration. In contrast, the compositions of the present invention do not generate by-products and generally only cause minor reversible effects at the injection site. This has been clearly observed in animals by visual inspection in necroscopy. Most of the signs of the deposit have disappeared, for example, 8-12 weeks after the i.m. injection. or s.c. In addition, due to the non-irritating nature of the formulations, it is possible to apply directly to the eyes and it has been observed that it does not cause irritation in a rabbit model.

The following are particular examples of octreotide formulations. In one embodiment of the invention, the pre-formulations as such are none of those cited in the table below. In alternative embodiments, these constitute highly preferred examples of compositions and to be used in aspects of the invention, particularly in previously filled articles, test kits, medical treatment methods and the use of compositions in the manufacture of a medicament.

Table 1

Relationships by weight:

Formulation

OCT EtOH PC GDO

X1

 2.4 10 36 54

X2

 6 10 36 54

X3

 0.5 10 36 54

Table 2% by weight

Formulation

OCT EtOH PC GDO1 GDO2 GDO3 TP DPPG

AND

2 10 35.2 - - 52.8 - -

F

 2 10 35.2 52.8 - - - -

G

2 10 25.2 - 52.8 - - -

H

2 10 26.4 - - - 61.6 -

I

one 10 35.6 53.4 - - - -

J

2 5 37.2 - - 55.8 - -

K

3 5 36.8 - - 55.2 - -

L

6 5 35.6 - - 53.5 - -

M

3 5 35.8 - - 55.2 - one

N

3 5 33.8 - - 55.2 - 3

OR

3 5 30.8 - - 55.2 - 6

P

3 5 46  - - 46  - -

Q

3 10 43.5 - - 43.5 - -

R

6 10 42  - - 42  - -

S

3 7 Four. Five  - - Four. Five  - -

T

 6 7 43.5 - - 43.5 - -

where OCT is octreotide, EtOH is ethanol, PC is LIPOID S100 soy phosphatidylcholine, GDO is glycerol dioleate, TP is -tocopherol, DOPG is dioleyl phosphatidylglycerol

GDO quality (according to AC)

 Monoglycerides

Diglycerides Triglycerides

GDO1

10.9% 87.5% 1.4%

GDO2

4.2%  92.1% 3.5%

GDO3

0.5%  95.3% 4.0%

In combination with the preferred features and characteristics indicated herein, the 14

pre-formulations of the invention may have one or more of the following preferred characteristics independently or in combination: They are not formulations as indicated in Tables 1 or 2; They are compositions as indicated in Tables 1 or 2; Component a) comprises, consists essentially or preferably consists of GDO;

Component b) comprises, consists essentially or preferably consists of soy PC; Component c) comprises, consists essentially or preferably consists of an alcohol of 1, 2, 3 or 4 carbon atoms, preferably isopropanol or more preferably ethanol;

The pre-formulation contains at least one somatostatin analog selected from those indicated herein. descriptive memory, preferably octreotide, lanreotide or vapreotide;

The pre-formulation has a low viscosity as indicated herein. The pre-formulation forms a liquid crystalline phase as indicated herein after a in vivo administration

The pre-formulation generates a deposit following an in vivo administration, which deposit at least one somatostatin analogue at a therapeutic level for a period of at least 30 days, preferably at least 40 days, more preferably at least 60 days.

In combination with the preferred features and characteristics indicated herein, the (or) the method (s) of treatment of the present invention may (n) have one or more of the following characteristics Preferred, independently or in combination:

The method comprises the administration of at least one formulation as indicated in Tables 1 or 2;

The method comprises the administration of at least one formulation with one or more preferred characteristics, as indicated above; The method comprises the administration of at least one formulation as indicated herein.

descriptive by injection i.m., s.c. or preferably s.c. deep

The method comprises an administration by means of a previously filled administration device, as indicated herein; The method comprises administration through a needle no larger than a 19 gauge, preferably more

smaller than a 19 gauge, more preferably 23 gauge;

The method comprises a single administration every 20 to 90 days, preferably 30 to 60 days, plus preferably 35 to 48 days. In combination with the preferred features and characteristics indicated herein, the

(or the) use (s) of the pre-formulations indicated herein in the manufacture of Medications may have one or more of the following preferred characteristics, independently or in combination:

The use comprises the use of at least one formulation as indicated in Tables 1 or 2;

The use includes the use of at least one formulation with one or more characteristics as indicated. previously; The use comprises the manufacture of a medicament for the administration of at least one formulation as

indicated herein by injection i.m., s.c. or, preferably, s.c. deep

The use comprises the manufacture of a medicament for administration by means of a device for pre-filled administration, as indicated herein; The use comprises the manufacture of a medicament for an administration through a ajuga no greater than

19 gauge, preferably smaller than 19 gauge, more preferably 23 gauge or smaller;

The use includes the manufacture of a drug for administration once every 20 to 90 days, preferably 30 to 60 days, more preferably 35 to 48 days. In combination with the preferred features and characteristics indicated herein, the

previously filled devices of the invention may have one or more of the following characteristics preferred, independently or in combination;

They contain at least one formulation as indicated in tables 1 or 2; They contain a preferred formulation as indicated herein; They comprise a smaller needle that is 19 gauge, preferably no larger than 23 gauge; They contain a single dose of 1 to 500 mg of somatostatin analog, preferably 5 to 300 mg; They contain octreotide, at approximately 10 to 180 mg; They contain octreotide at approximately 0.1 to 3 mg per day between scheduled administrations; They contain a total volume for an administration of not more than 5 ml, preferably not more than 3 ml,

preferably not more than 2 ml. In combination with the preferred features and characteristics indicated herein, the

test kits of the invention may have one or more of the following preferred characteristics, independently or in combination: They contain at least one formulation as indicated in tables 1 or 2; They contain a preferred formulation as indicated herein; They contain a previously filled device as indicated herein; They contain a needle no larger than 19 gauge, preferably no larger than 23 gauge; They contain a single dose of 1 to 500 mg of somastotatin analogue, preferably 5 to 300 mg; They contain octreotide, at approximately 10 to 180 mg; They contain octreotide at approximately 0.2 to 3 mg per day between scheduled administrations; They contain a total volume for an administration of not more than 5 ml, preferably not more than 3 ml, more

preferably not more than 2 ml.

They contain instructions for administration by a route and / or at a frequency as indicated herein. descriptive memory; They contain instructions for administration for use in a treatment method as described in the

Present descriptive report.

The invention will be further illustrated below by reference to the following examples not limiting and associated figures, in which: Figure 1 demonstrates the non-linear decrease in the viscosity of the pre-formulation after the addition of N-methyl

pyrrolidinone (NMP) and EtOH; Figure 2 shows the plasma concentration (in rats) of octreotide (OCT) for 28 days following

a subcutaneous injection of a depot formulation comprising PC / GDO / EtOH (36/54/10% p) which It contains 5 mg of OCT / g formulation, corresponding to 0.5% drug content. Figure 3 shows the plasma concentration (in rats) of octreotide (OCT) for 5 days following a

subcutaneous injection of a depot formulation comprising PC / GDO / EtOH (47.5 / 47.5 / 5.0% p). Figure 4 shows the octreotide in plasma during a period in Beagle dogs after a s.c.

15 mg (approx. 1.7 mg / kg) octreotide (3% drug content) in 0.5 ml of the formulation precursor P tank (PC / GDO / EtOH (47.5 / 47.5 / 5). Figure 5 shows concentrations of IGF-1 in plasma as% of baseline over time in dogs

Beagle after a dosage s.c. of 15 mg (approx. 1.7 mg / kg) of octreotide (3% drug content) in

0.5 ml of the precursor of the deposit formulation P. Figure 6 shows the plasma octreotide over time in rats after a s.c. of 30 mg / kg octreotide in 1 mg / kg of P, Q and S.

Figure 7 shows plasma octreotide over time in rats after a s.c. of 9, 30 and

90 mg / kg octreotide in 0.3, 1 and 3 mg / kg of formulation P; Y Figure 8 shows the concentration of plasma octreotide over time in dogs after a s.c. and i.m. 0.5 mg of formulation P.

Examples

Example 1

Availability of various liquid crystalline phases in the reservoir by choosing the composition

Injectable formulations were prepared containing different proportions of phosphatidylcholine ("PC" - Epikuron 5 200) and glycerol dioleate (GDO) and with EtOH as solvent to illustrate that various liquid crystalline phases can be accessed after balancing the precursor formulation tank with excess water.

Appropriate amounts of PC and EtOH were weighed in glass vials and the mixture was placed in a shaker until the PC dissolved completely to form a clear liquid solution. GDO was then added to form a homogeneous solution for injection.

10 Each formulation was injected into a vial and was equilibrated with excess water. The phase behavior was assessed visually and between cross values polarizes at 25 ° C. The results are presented in the following Table:

Formulation PC (% p) GDO (% p) EtOH (% p) Phase in H2O

A 22.5 67.5 10.0 L2 B 28.8 61.2 10.0 I2 C 45.0 45.0 10.0 HII D 63.0 27.0 10.0 L

L2 = inverted micellar phase

I2 = inverted cubic liquid crystalline phase

15 HII = inverted hexagonal liquid crystalline phase

L = laminar phase

Example 2

Viscosity in PC / GDO (6: 4) or PC / GDO (3: 7) after solvent addition (EtOH, PG and NMP).

A mixture of PC / GDO / EtOH was made according to the method of Example 1. All or almost all of the EtOH was separated from

The mixture with a rotary evaporator (vacuum, 40 ° C, 1h) and the resulting solid mixture was weighed into a glass vial after which 1, 5, 10 or 20% solvent (EtOH, propylene glycol (PG) or n-methylpyrrolidone (NMP)). The samples were allowed to equilibrate several days before measuring the viscosity at a shear rate of 0.1 s-1 with a Physica UDS 200 rheometer at 25 ° C.

This example clearly illustrates the need for a solvent with certain deposit precursors in order to

25 obtain an injectable formulation (see Figure 1). The viscosity of solvent-free PC / GDO mixtures increases with an increasing ratio of PC. Systems with a low PC / GDO ratio (plus GDO) are injectable with a lower solvent concentration.

Example 3: Preparation of a depot composition containing the octreotide peptide

The octreotide is a synthetic octa-peptide, usually provided as an acetate salt, and is similar to the

30 somatostatin hormone. Octreotide decreases the production of substances such as growth hormone, insulin and glucagons. It is used in the treatment of acromegaly and to reduce redness and watery diarrhea caused by metastatic cancerous tumors (carcinoid syndrome) or tumors called vasoactive intestinal peptide tumors (VIPomas).

24 mg or 60 mg of octreotide was dissolved in 0.1 g of EtOH. Subsequently, 0.36 g of PC and 0.54 g were dissolved.

35 of GDO in this solution and a depot formulation precursor was obtained. Injection of the precursor of the excess aqueous phase formulation (23G syringe; 0.6 mm x 30 mm) resulted in a monolithic liquid crystalline phase (structure I2). That is, octreotide (2.4% or 6.0%) did not alter the formation of the monolith or the behavior of the phases after exposure to an aqueous environment.

The octreotide deposit precursor formulations in this example were tested for

40 stability against crystallization during storage. Each formulation was stable at 4-8 ° C for at least two weeks.

Example 4: In vivo release study from a depot formulation containing octreotide administered subcutaneously.

In an in vivo rat model, octreotide drug release was followed for 28 days. The rats were surgically prepared by inserting a silicon catheter into the jugular vein. Two days after surgery, the formulations were administered subcutaneously in the dorsal region, slightly posterior to the scapula using a syringe (23G, 0.6 mm x 25 mm). The dose of octreotide was 10 mg / kg and the volume 1 5 ml / kg corresponding to a drug content of 1% octreotide in the precursor of the depot formulation (PC / GDO / EtOH (36/54/10) ). Blood samples were collected through the catheter for a period of 28 days (see Figure 2) and stabilized with EDTA. Aprotinin (500 KIE / ml of blood) and a protease inhibitor were added to the samples to prevent enzymatic degradation of octreotide during treatment. Octreotide concentration in rat plasma was determined using immunosorbent assay linked to

10 enzymes (ELISA).

From Figure 2 it appears that the investigated formulation provides a release profile essentially without a sharp increase effect (less than 10% OCT is released within 24 hours).

Therefore, Figure 2 shows the plasma octreotide over time in rats (n = 3) after a s.c. 10 mg / kg octreotide (1% drug content) in 1 ml / mg of the formulation precursor of

15 tank (PC / GDO / EtOH (36/54/10)).

The plasma octreotide concentration quickly reached its maximum value, after which plasma levels slowly decreased to a platform level in a few days. The "sharp increase" (initial release over the first 24 hours) was <10%. Data are presented as means típica standard deviation.

Example 5: Degradation of deposit formulation in the rat

20 Various volumes (1, 2, 6 ml / kg) of the deposit precursor (36% p of PC, 54% p of GDO and 10% p of EtOH) were injected into the rat and the size of the reservoir was measured in two perpendicular directions with a slip gauge for a period of 14 days. The deposit size was estimated as the corrected size for skin thickness. The baseline size was determined on day 3 after injection, after allowing the formulation and subcutaneous tissue to stabilize. It was found that the average diameter of the tank

25 was reduced by approximately 20% for 14 days and that substantial amounts of the formulations were still present subcutaneously in the rat after this time, see Table.

Average diameter of deposit monolith.

Dose (ml / kg)

Average diameter on day 3 (mm) Average diameter on day 14 (mm)

1 (n = 3)

15.8 12.5

2 (n = 3)

18.5 15.3

6 (n = 3)

23.3 19.3

Example 6: Additional examples of viscosity in PC / GDO mixtures after the addition of co-solvent

30 PC / GDO mixtures and co-solvent were prepared according to the methods of Example 1 and Example 2 in the proportions indicated in the following table. The samples were allowed to equilibrate for several days before making the viscosity measurements using a Physica UDS 200 rheometer at 25 ° C.

Sample

PC / GDO (p / p) EtOH% p Glycerol /% p Viscosity / mPas

one

50/50 3 - 1900

2

50/50 5 - 780

3

50/50 7 - 430

4

50/50 8 - 300

5

50/50 10 - 210

6

50/50 fifteen - 100

7

45/55 3 - 1350

8

45/55 5 - 540

9

45/55 7 - 320

Sample

PC / GDO (p / p) EtOH% p Glycerol /% p Viscosity / mPas

10

 45/55 8 - 250

eleven

 45/55 10 - 150

12

45/55 fifteen  - 85

13

 40/60 3 - 740

14

 40/60 5 - 400

fifteen

 40/60 7 - 240

16

 40/60 8 - 200

17

 40/60 10 - 130

18

40/60 fifteen  - 57

19

 40/60 - 19 8x106

twenty

 40/60 - - 2.5x108

twenty-one

 40/60 - - 4x107

This example further illustrates the need for a solvent with viscosity decrease properties in order to obtain injectable formulations. Mixtures containing glycerol (sample 19) or water (samples 20 and 21) are too viscous to be injectable at solvent concentrations equivalent to samples containing EtOH (compare samples 13, 14 and 17).

Example 7: Octreotide Formulations Compositions

Formulations were prepared as in Example 1 by mixing the active octreotide peptide with a mixture of GDO (at one or several levels of purity) or tocopherol, PC, ethanol and optionally dioleyl-PG in the following proportions (by weight)

Formulation

OCT EtOH PC GDO1 GDO2 GDO3 TP DOPG

AND

2 10 35.2  - - 52.8  - -

F

 2 10 35.2 52.8 - - - -

G

2 10 35.2 - 52.8 - - -

H

2 10 26.4  - - - 61.5 -

I

one 10 35.6 53.4 - - - -

J

2 5 37.2  - - 55.8  - -

K

3 5 36.8  - - 55.2  - -

L

6 5 35.6  - - 53.5  - -

M

3 5 35.8  - - 55.2  - one

N

3 5 33.8  - - 55.2  - 3

OR

3 5 30.8  - - 55.2  - 6

P

3 5 46  - - 46  - -

Q

3 10 43.5  - - 43.5  - -

R

6 10 42  - - 42  - -

S

3 7 Four. Five  - - Four. Five  - -

T

6 7 43.5  - - 43.5  - -

where OCT is octreotide acetate, EtOH is ethanol, PC is LIPOID S100 soy phosphatidylcholine, GDO is glycerol dioleate, TP is to-tocopherol, DOPG is dioleyl phosphatidylglycerol.

Formulation

 OCT EtOH PC GDO3

OR

3.5 5 45.75 45.75

V

4.68 5 45.16 45.16

X

5 5 Four. Five Four. Five

Y

5.84 5 44.58 44.58

in which OCT is octreotide acetate, EtOH is ethanol, PC is LIPOID S100 soy phosphatidylcholine, GDO is glycerol dioleate.

Formulation

 OCT EtOH PC GDO3

Z

 3.5 5 45.75 45.75

AA

4.68 5 45.16 45.16

BB

5 5 Four. Five Four. Five

DC

 5.84 5 44.58 44.58

in which OCT is octreotide acetate, EtOH is ethanol, PC is LIPOID E80 egg phosphatidylcholine, GDO is 10 glycerol dioleate.

GDO quality (according to AC)

 Monoglycerides

Diglycerides Triglycerides

GDO1

10.9% 87.5% 1.4%

GDO2

4.2%  92.1% 3.5%

GDO3

0.5%  95.3% 4.0%

Formulation P (for the composition see above) was administered by injection s.c. in the rat at a level of 1 ml of formulation per kg of body weight, corresponding to 30 mg / kg of octreotide.

15 Octreotide plasma levels after administration were checked 5 days to examine any profile of sharp increase. It was observed that the highest plasma concentration was less than three times more than the average plasma concentration over the first 5 days.

The results of the study are shown in Figure 3

Example 8 - A 6-week study of octreotide deposition in dogs:

20 The objective of this study was to assess the baseline pharmacokinetic data of octreotide. Pre-formulation P was used as described in Example 7.

The study was conducted in 3 male and 3 female Beagle dogs (approximately 5 months old). The dogs were dosed s.c. in the neck with the formulation containing octreotide (0.5 ml of dosing volume, 30 mg of octreotide per ml).

25 Blood was collected from the biyugular funnel for analysis for 42 days (in total 20 samples) and stabilized with EDTA. Aprotinin (500 KIE / ml of blood) was added to the samples to prevent degradation of octreotide during treatment.

Octreotide plasma levels (OCT) and insulin crediting factor 1 (IGF-1) at each time value were measured using enzyme-linked immunosorbent assay methods (ELISA) and the results are shown in Figures 4 and 5. It was observed that octreotide levels remained above the level of 1

ng / ml until the end of the 42-day study, indicating a potentially therapeutic dose for the entire 6-week trial. The concentration of IGF-1 in plasma was significantly reduced on day 1 and remained reduced throughout the entire study.

Figure 4 therefore shows the plasma octreotide over time in Beagle dogs (3 males + 3 females) after a s.c. of 15 mg (approx. 1.7 mg / kg) of octreotide (3% drug content) in 0.5 ml of the precursor of the reservoir formulation P 8PC / GDO / EtOH (47.5 / 47.5 / 5). The plasma octreotide concentration quickly reached its maximum value, after which plasma levels slowly decreased to a platform level in a few days. The "sharp increase" (initial release over the first 24 hours) was <10% and the platform was reached in 24 hours. Data are presented as means típica standard deviation.

Figure 5 shows the concentrations of IGF-1 in plasma as% of baseline over time in Beagle dogs (3 male + 3 females) after a s.c. of 15 mg (approx. 1.7 mg / kg) of octreotide (3% drug content) in 0.5 ml of the precursor of the depot formulation P (PC / GDO / EtOH (47.5 / 47.5 / 5) The IGF-1 reached its minimum value in 5 days and then remained below the baseline values for the rest of the trial period, indicating that octreotide continuously decreased the synthesis / release of this hormone. Data are presented as means típica standard deviation.

In contrast to PLGA formulations, no period of detention was observed between injection and the effects on octreotide and IGF-1 levels. The initial release was less than 10% and the plasma octreotide platform level was reached in 24 hours.

Example 9 - Variation of the “sharp increase” profile

The initial release profile of three otherwise identical deposit precursors was examined using the compositions Q, S and P generated in Example 7. Each of the formulations was injected into a rat model by the protocol described in Example 4 This experiment was performed for 28 days.

The release from the three formulations varied significantly in the first 5 days and is shown in Figure

6. Therefore, this figure shows plasma octreotide over time in rats after dosing.

s.c. 30 mg / kg octreotide (3% drug content) in 1 ml / kg of the precursors of the formulations P (PC / GDO / EtOH (47.5 / 47.5 / 5), Q (PC / GDO / EtOH (45/45/10) and S (PC / GDO / EtOH (46.5 / 46.5 / 7), respectively. N = 6 in all groups.

It was found that the composition, particularly EtOH (component c) could be used to refine the initial release profile of octreotide. For formulation P (5% EtOH), the initial release was less than 10% and the platform was reached in 12 hours. For Q and S, the initial releases were> 10% and the platform was not reached until after 48 hours. The data in the Figure are presented as means típica standard deviation.

All three compositions showed essentially the same release profiles from day 5 until the end of the study (day 28).

Example 10 - Variable injection volume

Composition P generated in Example 7 was administered in three injection volumes to study the dose ratio to plasma concentration. The protocol for administration in the rat model was as for Example 4 and the results are shown in Figure 7.

Therefore, Figure 7 shows the plasma octreotide over time after a s.c. of 9, 30 and 90 mg / kg octreotide (3% drug content) in 0.3, 1 and 3 ml / kg of the precursor of the formulation P 8PC / GDO / EtOH (47.5 / 47.5 / 5), respectively. N = 8 in all groups.

The initial release was less than 10% and the platform was reached in 48 hours for all doses. There was an unexpected proportionality between the volume of the dose (dose) and the concentration of octreotide in plasma (and area under the plasma concentration curves versus time). The data in the figure are presented as means típica standard deviation.

Legends of the figures:

Figure 1. Decrease in viscosity in the deposit precursor after the addition of dissociants. PC / GDO (6/4) as a precursor for an inverted hexagonal HII phase and PC / GDO (3/7) is a precursor for an inverted cubic I2 phase.

Figure 2. Concentration of octreotide in plasma over 28 days in rats (n = 3) after dosing

s.c.

 of 1 ml / kg of formulation J (1% p of OCT). Data as means with typical deviations.

Figure 3. Concentration of octreotide in plasma over 28 days in rats (n = 6) after dosing

s.c.

 of 1 ml / kg of formulation P (3% p of OCT).

Figure 4. Concentration of octreotide in plasma in the range of 1 hour to 42 days in dogs (n = 6) after a s.c. 0.5 ml of formulation P (3% p of OCT).

Figure 5. Concentration of IGF-1 in plasma in the range of 1 hour to 42 days in dogs (n = 6) after a s.c. 0.5 ml of formulation P (3% p of OCT).

Figure 6. Concentration of octreotide in plasma over 5 days in rats after a s.c. of 1 mg / kg of formulation P (n = 6), Q (n = 6) and S (n = 6), respectively. All formulations contained 3% p of 5 OCT.

Figure 7. Concentration of octreotide in plasma over 28 days in rats after a s.c. of formulation P (3% p of OCT) provided as different dosing volumes of 0.3, 1 and 3 ml / kg. N = 6 for all treatments.

Figure 8. Concentration of octreotide in plasma over 6 days in dogs (n = 6) after dune dosing 10 s.c. and im. 0.5 mg of P formulation (3% p OCT).

Claims (20)

1. A pre-formulation, comprising a low viscosity mixture of: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; 5 c) at least one organic solvent containing oxygen; d) 0.1-10% p of at least one somatostatin analog in which the ratio of a: b is in the range of 40:60 to 70:30; and in which the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure after coming into contact with an aqueous fluid. 2. A pre-formulation according to claim 1, wherein component a) comprises GDO. 3. A pre-formulation according to claim 1 or claim 2, wherein component b) comprises: i) Soybean PC and / or ii) Egg PC. 4. A pre-formulation according to any one of claims 1 to 3, wherein component c) comprises eta15 nol.

5.

 A pre-formulation according to any one of claims 1 to 4, wherein said pre-formulation comprises at least one somatostatin analog selected from octreotide, lanreotide and vapreotide.

6.

 Use of:

a) at least one diacyl glycerol; B) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; Y d) 0.1-10% p of at least one somatostatin analog; in which the ratio of a: b is in the range of 40:60 to 70:30; in the manufacture of a low viscosity pre-formulation medicament for use in in vivo formation 25 of a reservoir for the treatment of acromegaly, cancers, carcinomas and melanomas, tumors that express at least one somatostatin receptor, sst (2) -positive tumors, sst (5) -positive tumors, prostate cancers, gastro-whole neuroendocrine tumors -pancreatic (NE GEP), carcinoid tumors, insulinomas, gastrinomas, vasoactive intestinal peptide tumors (VIP) and glucagonomas, high growth hormone (GH), high insulin growth factor I (IGF-I), variceal bleeding ( especially esophageal), gastro-intestinal problems 30 induced by chemotherapy (such as diarrhea), lymphorerrhea, diabetic retinopathy, thyroid eye disease, obesity, pancreatitis and / or related conditions. 7. The use according to any of claims 6, which comprises the use of at least one formulation as claimed in any one of claims 1 to 5. 8. The use as claimed in any of claims 6 or 7, which comprises the manufacture of a medium for administration by i) i.m. injection. ii) injection s.c. iii) injection s.c. deep iv) intravitreal v) subconjunctival injection; vi) or other routes of parenteral administration.

9.

 The use as claimed in any one of claims 6 to 8, which comprises the manufacture of a medicament for administration by means of a pre-filled administration device.

10.

 The use as claimed in any of claims 6 to 9, which comprises the manufacture of a medicament for administration through a needle no larger than 19 gauge.

eleven.

 The use as claimed in any one of claims 6 to 10, which comprises the manufacture of a medicament for administration once every 20 to 90 days.

12.

 A disposable delivery device previously loaded with a measured dose of a pre-formulation comprising a mixture of low viscosity of: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen;

d) 0.1-10% p of at least one somatostatin analog; in which the ratio of a: b is in the range of 40:60 to 70:30.

13.

 The device of claim 12, which is a syringe or syringe barrel.

14.

 The device of any of claims 12 or 13, which contains a formulation as claimed in claims 1 to 5.

fifteen.

 The device of any of claims 12 to 14, comprising a needle no larger than 19 gauge.

16.

 The device of any of claims 12 to 15, containing a single dose of 1 to 500 mg of somatostatin analog.

17.

 The device of any of claims 12 to 16, which contains a total volume for administration of no more than 5 ml.

18.

 A test kit for the administration of at least one somatostatin analog, said test kit containing a measured dose of a formulation comprising a low viscosity mixture of: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one organic solvent containing oxygen; Y

d) 0.1-10% p of at least one somatostatin analog in which the ratio of a: b is in the range of 40:60 to 70:30.

19.

 The test kit of claim 18, which contains a formulation as claimed in any one of claims 1 to 5.

twenty.

 The test kit of any of claims 18 or 19, which contains a prefilled device as claimed in any one of claims 12 to 17.

twenty-one.

 The test kit of any one of claims 14 to 19, containing a single dose of 1 to 500 mg of somatostatin analog.