RU2777554C2 - Octreotide injection - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention relates to a sterile solution for the treatment of diseases selected from acromegaly, carcinoid tumor, vasoactive intestinal peptide tumor, and combinations thereof, containing: octreotide in the form of pharmaceutically acceptable salt, present at a concentration equivalent from 2.0 to 2.5 mg/ml of a base of octreotide, mannitol at a concentration in the range from 20.0 to 25.0 mg/ml, and phenol, in a pharmaceutically acceptable carrier, such as water for injections, where the sterile solution is present in an injection device.

EFFECT: present invention provides for satisfactory bioavailability of octreotide in the form of salt.

10 cl, 5 tbl, 2 ex, 2 dwg

Description

Technical field

The present invention relates to a sterile solution of octreotide in the form of a pharmaceutically acceptable salt loaded into an injection device, wherein the octreotide salt is present at a concentration equivalent to 2.0 to 2.5 mg/ml octreotide base.

Prior Art

Octreotide is commercially available under the brand name Sandostatin™ as preservative-filled sterile 5 ml multi-dose vials in two concentrations of 200 µg/ml and 1000 µg/ml. The present inventors have previously developed a multi-dose pen containing an octreotide acetate solution that allows patients to self-administer a dose of octreotide as described in US Patent Application Pub. No. 20140213984 A1. During this time, the inventors of the present invention worked on the creation of an injection device, such as a syringe pen, with multiple doses, providing daily doses of octreotide for about one month or so. In particular, attempts were made to develop an octreotide solution that had a 5-fold higher concentration, i.e. 5 mg/ml compared to the Sandostatin™ product vial, so that the injection volume was reduced by a factor of five. Advantageously, since the concentration of octreotide was increased by a factor of five, the volume required to deliver an equivalent dose was reduced by a factor of five, and accordingly, the amount of preservative added was reduced by a factor of five.

It is well known that peptide drugs after oral or parenteral administration exhibit poor bioavailability in the blood, for example, due to their short biological half-lives, caused in turn by their metabolic instability (see the disclosure in US patent No. 5,538,739). The present inventors have encountered the same problem of poor bioavailability for octreotide as disclosed in the prior art.

An aqueous solution of octreotide acetate at a concentration equivalent to 5 mg/ml octreotide base (as described in Example 1 of US20140213984 A1), which was filled into a pen, was administered subcutaneously in a volume of 20 microliters to human volunteers. The relative bioavailability of octreotide acetate was determined and compared to Sandostatin™ solution, which has a concentration of 1 mg/mL octreotide acetate prepared in a volume of 100 microliters and administered via a conventional syringe. Surprisingly, the octreotide acetate test sample provided only 5% relative bioavailability compared to the Sandostatin™ solution.

Thus, the aim of the present invention is to solve the technical problem of the poor bioavailability of octreotide in salt form.

The present inventors found a specific concentration range of 2.0 to 2.5 mg of octreotide base per ml of solution, which surprisingly provided a satisfactory bioavailability equivalent to 1 mg/ml of Sandostatin™ solution at the same dose.

Brief description of the invention

The present invention provides a sterile solution containing octreotide in the form of its salt, present at a concentration equivalent to 2.0 to 2.5 mg/ml of octreotide base, and at least one preservative, in a pharmaceutically acceptable carrier, wherein the solution is present in a device for injections.

Brief description of graphic materials

Figure 1 is a plot of mean plasma octreotide concentration (pg/mL) versus time (hour) for test product (A) and control (C) according to Example 2.

Figure 2 is a plot of mean plasma octreotide concentration (pg/mL) versus time (hour) for test product (B) and control (C) according to Comparative Example 1.

Detailed description of the invention

As used herein, the term "bioavailability" generally refers to the rate and extent to which the active ingredient, ie octreotide, is absorbed from the injection site and becomes available to the parenteral circulation.

The present invention discloses the following unexpected results: (1) subcutaneous administration of a solution of octreotide base in the form of its salt having a concentration of 5.0 mg/ml, when administered subcutaneously at a dose of 100 micrograms at an injection volume of 20 microliters through a syringe pen, provided a bioavailability that was significantly lower than the bioavailability provided by subcutaneous administration of the same dose of control solution (1 mg/ml Sandostatin™ octreotide solution) administered with a conventional syringe and (2) in a similar study when a solution of octreotide base in its salt form having concentration of 2.5 mg/mL, administered subcutaneously at a dose of 100 micrograms at a 40 microliter injection volume via a pen, the observed bioavailability was surprisingly equivalent to that provided by the same dose of control solution (1 mg/mL Sandostatin™ octreotide solution) administered at an injection volume of 100 microliters through a conventional syringe.

Thus, the present invention relates to a sterile solution containing: octreotide in the form of a pharmaceutically acceptable salt, present at a concentration equivalent to 2.0 to 2.5 mg/ml of octreotide base, and at least one preservative, in a pharmaceutically acceptable carrier, wherein the sterile solution is present in the injection device. This sterile solution containing octreotide in salt form, when administered subcutaneously to a human through an injection device, provides equivalent bioavailability to that obtained by injecting the same dose of octreotide by injecting a commercially available solution of 1 mg/mL Sandostatin™ through a conventional injection system as syringe with a needle.

In some preferred embodiments, salts of octreotide include pharmaceutically acceptable salts such as acid addition salts. Acid addition salts can be formed with an inorganic acid, an organic acid, or a polymeric acid, such as hydrochloric acid, acetic acid, lactic acid, citric acid, fumaric acid, malonic acid, maleic acid, tartaric acid, aspartic acid, benzoic acid, succinic acid. or pamoic acid. This includes the simple salt forms of octreotide, for example, octreotide acetate, octreotide lactate, and octreotide maleate; less water-soluble salt forms of octreotide, for example, pamoate salt forms of octreotide and octreotide fatty acid salts, for example, octreotide palmitate and octaotide stearate. According to embodiments, acid addition salts may exist as monovalent or divalent salts, depending on whether 1 or 2 equivalents of acid are added. In one preferred embodiment, the octreotide salt is octreotide acetate.

According to the present invention, the sterile solution contains octreotide in the form of a pharmaceutically acceptable salt present at a concentration equivalent to 2.0 to 2.5 mg/ml octreotide base, e.g. , 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.15, 2.2, 2.25, 2.3, 2 .35, 2.4, 2.45 or 2.50 mg/ml octreotide base. In one embodiment, the sterile solution contains octreotide in salt form at a concentration ranging from 2.01 to 2.50 mg per ml of octreotide base. In another embodiment, the sterile solution contains octreotide in the form of its salt at a concentration ranging from 2.1 to 2.5 mg per ml of octreotide base. In one particularly preferred embodiment, the sterile solution contains octreotide in salt form at a concentration equivalent to 2.5 mg per ml of octreotide base.

In one preferred embodiment, the present invention relates to a sterile solution containing octreotide acetate present at a concentration equivalent to 2.0 to 2.5 mg/ml of octreotide base and at least one preservative, in a pharmaceutically acceptable carrier, wherein the solution is present in an injection device such as a pen.

Preferably, the injection device is a multiple dose pen containing: a cartridge of sterile octreotide solution in the form of a reservoir, in volume ranges selected from: 1.0 to 10.0 ml, preferably 2.0 to 5.0 ml, more preferably 2.5 to 3.5 ml and 2.8 to 3.2 ml; specific volumes selected from, for example, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4 or 3, 5 ml. In one preferred embodiment, the volume of solution contained in the injection device is in the range of 2.8 to 3.2 ml.

A portion of the sterile solution from the injection device is administered to deliver a specific dose to the patient, and the total solution contained in the injection device is suitable for delivering multiple daily doses on consecutive days throughout the course of therapy.

In preferred embodiments, the injection device is configured to administer 20 to 250 microliters of solution to provide octreotide in an amount in the range of 40 to 625 micrograms per injection. In one or more embodiments, the injection device is configured to administer in a single injection a volume in the range of about 20 to 250 µl, for example, 20 µl, 25 µl, 30 µl, 35 µl, 40 µl, 45 µl, 50 µl µl, 60 µl, 65 µl, 70 µl, 75 µl, 80 µl, 85 µl, 90 µl, 95 µl, 100 µl, 125 µl, 150 µl, 175 µl, 200 µl or 225 µl, preferably about 20 to about 80 µl. In preferred embodiments, the present invention provides 20 to 80 microliters of sterile solution per injection, such as 20, 40, 60 or 80 microliters to deliver a dose of octreotide in the range of 50 to 200 micrograms per injection, such as 50, 100, 150 or 200 mcg per injection.

In one preferred embodiment, the present invention relates to a sterile solution containing octreotide acetate present at a concentration equivalent to 2.0 to 2.5 mg/ml of octreotide base and at least one preservative, in a pharmaceutically acceptable carrier, wherein the solution is present in an injection device in volumes in the range of 2.0 to 5.0 ml and, further, where the injection device is configured to administer to the patient from 20 to 250 μl of the solution per injection to provide octreotide in an amount in the range of 40 to 625 μg per injection

In a particularly preferred embodiment, the present invention relates to a sterile solution containing octreotide acetate present at a concentration equivalent to 2.5 mg/ml octreotide base and at least one preservative, in a pharmaceutically acceptable carrier, wherein the solution is present in a device for injection into volumes in the range of 2.0 to 3.0 ml; and further, wherein the injection device is configured to administer 20 to 80 microliters of solution per injection to the patient to provide octreotide in an amount in the range of 50 to 200 μg per injection.

In one particularly preferred embodiment, the present invention relates to a sterile solution containing octreotide acetate present at a concentration equivalent to 2.5 mg/ml octreotide base and at least one preservative, in a pharmaceutically acceptable carrier, wherein the solution is present in a pen and, further, wherein when administering 40 μl of the solution through a pen, a dose equivalent to 100 μg of octreotide base per injection is administered.

In another preferred embodiment, the present invention relates to a sterile solution containing octreotide acetate present at a concentration equivalent to 2.5 mg/ml of octreotide base and at least one preservative, in a pharmaceutically acceptable carrier, wherein the solution is present in a pen and , additionally, where with the introduction of 80 μl of the solution through a syringe pen, a dose equivalent to 200 μg of octreotide base per injection is injected.

In another embodiment, the present invention relates to a sterile solution containing octreotide acetate present at a concentration equivalent to 2.5 mg/ml octreotide base and at least one preservative, in a pharmaceutically acceptable carrier, wherein the solution is present in a pen and, additionally, where with the introduction of 60 μl of the solution through a syringe pen, a dose equivalent to 150 μg of octreotide base per injection is injected.

In preferred embodiments, the desired volume of sterile solution, based on the desired dose, can be accurately administered using a specific dose dialer present in the injection device. The injection device may have corresponding unit labels in the dose dial window ranging from 40 to 625, such as, for example, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325 .

In one or more embodiments, a different dose of octreotide may be administered using a different volume of an aqueous solution of octreotide acetate, such as, for example, a 100 μg dose may be administered by injecting 50 μl of a sterile solution containing 2.0 mg/ml of octreotide base, or alternatively by administering 40 µl of a solution containing 2.5 mg/ml octreotide base, or alternatively by injecting 45.5 µl of a solution containing 2.2 mg/ml octreotide base. Similarly, a 200 µg dose can be administered by injecting a 100 µl sterile solution containing 2.0 mg/ml octreotide base, or alternatively by injecting 80 µl of a solution containing 2.5 mg/ml octreotide base, or alternatively by injecting 91 µl of a solution containing 2.2 mg/ml octreotide base.

In one particularly preferred embodiment, the sterile solution of octreotide, or a pharmaceutically acceptable salt thereof, comprises:

where the solution further contains a preservative, and the pH of the solution is in the range from 3.9 to 4.5. Additionally, the sterile solution is contained in an injection device such as a pen. In one preferred aspect, the preservative is phenol and is present at a concentration of about 5 mg/ml.

In another preferred embodiment, the sterile solution of octreotide or a pharmaceutically acceptable salt thereof comprises:

where the solution further contains a preservative, and the pH of the solution is in the range from 3.9 to 4.5. Additionally, the sterile solution is contained in an injection device such as a pen. In one preferred aspect, the preservative is phenol and is present at a concentration of about 5 mg/ml.

In a specific embodiment, the present invention relates to a sterile solution containing: octreotide acetate present at a concentration equivalent to 2.5 mg/ml octreotide base and at least one preservative, in a pharmaceutically acceptable carrier, wherein the sterile solution is present in an injection device in a volume of 2.8 to 3.0 ml and, additionally, where the injection device is configured to administer 20, 40, 60 and 80 microliters of solution per injection to the patient to deliver octreotide in an amount of 50 μg, 100 μg, 150 μg and 200 mcg per injection, respectively. This sterile solution, when administered subcutaneously via a human/patient injection device, provides a bioavailability (i.e. C _max , AUC _0-t , AUC _0-∞ ) equivalent to that obtained when the same dose of octreotide is administered by subcutaneous injection of a commercially available solution octreotide 1 mg/mL (Sandostatin™) administered through a conventional syringe and needle injection system. The sterile solution of these preferred embodiments further contains phenol as a preservative present at a concentration in the range of 4 to 5 mg/mL and mannitol as an isotonicity agent present in a concentration in the range of 20.0 to 25.0 mg/mL. ml, preferably at a concentration of 22.5 mg/ml. It has been established that C _max , AUC _0-t and AUC _0-∞ observed with subcutaneous administration of a sterile solution of the present invention through a syringe pen, are in the range from 85 to 115% of the value observed after subcutaneous administration of the same dose of octreotide by injection of a commercially available solution of octreotide 1 mg/mL (Sandostatin™) via a conventional syringe-and-needle injection system.

Alternatively, in another aspect, the present invention may provide an injection device comprising a sterile solution of octreotide, comprising octreotide in salt form and present at a concentration equivalent to 2.0 to 2.5 mg/ml octreotide base, and at least one preservative. , in a pharmaceutically acceptable carrier.

In one embodiment, the present invention relates to an injection device containing multiple doses of octreotide in the form of a sterile solution of octreotide, wherein the sterile solution contains an octreotide salt present at a concentration equivalent to 2.0 to 2.5 mg/ml of octreotide base, and at least one preservative in a pharmaceutically acceptable carrier, wherein the injection device is configured to administer 20 to 250 microliters of solution per injection to provide multiple doses of octreotide in an amount in the range of 40 μg to 625 μg per injection.

In one preferred embodiment, the present invention provides an injection device containing multiple doses of octreotide in the form of a sterile solution of octreotide acetate, wherein the sterile solution contains octreotide acetate, which is present at a concentration equivalent to 2.0 to 2.5 mg/ml octreotide base , and at least one preservative, in a pharmaceutically acceptable carrier, wherein the injection device is configured to administer 20 to 80 microliters of solution per injection to provide multiple doses of octreotide in an amount in the range of 40 μg to 200 μg per injection.

In one particularly preferred embodiment, the present invention provides an injection device containing multiple doses of octreotide in the form of a sterile solution of octreotide acetate, wherein the sterile solution contains octreotide acetate present at a concentration equivalent to 2.5 mg/ml octreotide base and at least one a preservative in a pharmaceutically acceptable carrier, wherein the injection device is configured to administer 20, 40, 60, or 80 microliters of solution per injection to provide multiple doses of octreotide in amounts of 50 μg, 100 μg, 150 μg, or 200 μg per injection, respectively.

The injection device according to the present invention may be a single or multiple dose injection device. This means that the reservoir or cartridge of the injection device contains a solution of octreotide acetate in a volume equivalent to a single dose, or in a volume equivalent to multiple doses. The injection device may be reusable or disposable. Preferably, the injection device is a device that is suitable for self-administration by a patient of a sterile drug solution. The injection device of the present invention may be selected from, but not limited to, a pen, an auto-injector, or a pre-filled syringe.

In preferred embodiments, the injection device is a pen. The pen syringe includes an upper housing that is connected to a cartridge holder holding the cartridge and a cap covering the cartridge holder. The tip of the cartridge holder has a threaded element with the possibility of attaching a standard syringe pen needle. The upper part of the housing is a combination of components that allows you to select a specific dose and enter the solution. The cartridge acts as the main drug reservoir containing the octreotide acetate solution. Preferably, the pens are multiple dose injection devices in which the cartridge contains multiple doses of a drug solution and the pen is suitable for delivering multiple injections or doses of drug until the cartridge is empty. The syringe pen is not limited in functionality and design and may have a different design.

The pen syringe according to one embodiment of the present invention is preferably designed to be suitable for subcutaneous administration of the active substance, which can be achieved by insertion of a hypodermic needle suitable for subcutaneous injection. The pen in accordance with one embodiment of the present invention preferably contains a structural device, for example, a control set or a dose dial device in the upper part of the housing, with which a certain dose of octreotide to be administered can be selected or adjusted (for example, by selecting a certain amount of injection in combination with a known concentration of octreotide present in the solution) by the physician, medical staff or, in the case of self-administration, by the patient. Thus, in this embodiment, the present invention also offers the possibility of selecting, if desired, intermediate doses for which no other storage containers or injection devices, in particular no other injection vials or ready-made syringes, are commercially available. In preferred embodiments, the pen has a dosing device having a dose display with a pointer, a dose setting knob that allows the user to select a particular dose, and a dose button that, when pressed, delivers the dose to the patient. In most preferred embodiments, the pen has a dose selection knob with an initial setting of "0" µg and four dose settings that allow the user to select the desired standard dose of 50, 100, 150, or 200 µg.

To deliver a dose of octreotide with a multidose pen, the user needs to attach a new needle to the tip of the cartridge holder, refill the pen before first use, select the dose to be administered on the dose dial, insert the needle subcutaneously into the patient's body at a predetermined injection site and inject the sterile solution by pressing the dose release button. If this is the first use, the user must refill the pen before use. The dosing device allows you to refill the pen with multiple doses before the first use.

In some embodiments, according to the present invention, the injection device is an auto-injector. Preferably, the auto-injector is designed to deliver a single dose of drug, ie octreotide acetate. The auto-injector may contain a pre-filled syringe or cartridge as a drug reservoir and may be disposable or reusable. In one embodiment, the auto-injector contains a pre-filled syringe in a disposable embodiment. In another embodiment, the auto-injector has a replaceable cartridge in a refillable version.

The auto injector can have a different design. An auto injector according to one embodiment of the present invention is preferably constructed such that it comprises the following components: a central assembly or body portion that is suitable for receiving a pre-filled syringe, a pre-filled syringe containing a reservoir, such as a cartridge or cartridge, in which an aqueous solution is stored, a reservoir with a protruding needle at one end and a piston stroke limiter at the other end.

The central part of the housing may be made of plastic or polymer material and may have a transparent viewing window through which the solution in the tank is visible. The auto-injector may further comprise a front assembly having a cap portion that holds the needle sheath or tip cap and is attached to a central assembly covering the protruding needle and sealing the needle tip opening. The auto-injector may further comprise a rear assembly, which may have a spring assembly, a plastic rod, and an activation button. During self-injection of the aqueous solution, the cap, together with the needle guard, must be removed from the body part, exposing the needle, and then after placing the body part of the auto-injector at the injection site, the activation button must be pressed to push the plastic rod with the spring assembly towards the piston stroke stop . This will affect the delivery of the aqueous solution through the needle to the patient.

The sterile solution of the present invention contains at least one preservative. Examples of suitable preservatives that can be used include, but are not limited to, phenol, benzyl alcohol, m-cresol, methylparabens, propylparaben, butylparaben, chlorobutanol, thimersal, phenylmercuric salts, and the like, or mixtures thereof.

The pharmaceutically acceptable carrier of the present invention contains an aqueous carrier such as water for injection. It may further contain one or more pH adjusting agents, buffering agents, isotonicity adjusting agents, or chelating agents.

In one embodiment, the pH of the sterile solution is in the range of 3.9 to 4.5. The pH can be adjusted within this range with pH adjusting agents such as sodium bicarbonate, lactic acid, hydrochloric acid, acetic acid, sodium hydroxide and the like. A buffering agent or buffer system may be used to maintain the pH in the desired range. Suitable buffers that can be used include, but are not limited to, lactate buffer, acetate buffer, citrate buffer, gluconate buffer, tartrate buffer, phosphate buffer, and the like. In preferred embodiments, the sterile solution contains lactic acid at a concentration of 3 to 4 mg/ml, preferably 3.4 mg/ml, and sodium bicarbonate is used to adjust the pH in the range of 4.2±0.3.

In preferred embodiments, the osmolality of the sterile solution is in the range of 220 to 290 mOsm/kg, preferably 230 to 280 mOsm/kg. Within this range, osmolality can be controlled by an isotonicity adjusting agent. Typical isotonicity agents that can be used in the sterile solution include, but are not limited to, mannitol, sorbitol, sodium chloride, potassium chloride, lactose, sucrose, maltose, trehalose, dextrose, and mixtures thereof. In a preferred embodiment, mannitol is used as an isotonicity agent and is preferably present in a sterile solution in an amount of 20.0 to 25.0 mg/ml solution. In the most preferred embodiment, the sterile solution contains 22.5 mg/ml mannitol as an isotonicity agent. The sterile solution may optionally contain a chelating agent such as disodium edetate, edetic acid, ethylenediaminetetraacetic acid, and the like.

In one preferred embodiment, phenol is used as a preservative in an amount of about 2.0 to 6.0 mg/ml solution, preferably about 4.0 to 5.0 mg/ml solution. In one specific embodiment, the solution contains octreotide in the form of its salt at a concentration of 2.5 mg of octreotide per ml of solution and about 4.0 to 5.0 mg per ml of phenol as a preservative. In another embodiment, a preservative that may be used is benzyl alcohol and is present in an amount of about 7.0 to 12.0 mg/mL of solution. In one particular embodiment, the solution contains octreotide in salt form at a concentration of 2.5 mg of octreotide per ml of solution and about 9.0-11.25 mg per milliliter of benzyl alcohol. In another embodiment, the preservative is m-cresol and is present in an amount of about 1.5 to 9.0 mg/ml solution, preferably about 2.0 to 4.0 mg/ml solution. In another embodiment, the preservative is methyl paraben and is present in an amount of about 0.1 to 4.0 mg/ml, preferably in an amount of 0.65 to 2.5 mg/ml of solution. In another embodiment, the preservative is propylparaben and is present in an amount of from about 0.05 to 2.0 mg/ml of solution, preferably in an amount of 0.2 mg/ml. In another embodiment, the preservative is butylparaben and is present in an amount of from about 0.06 to 1.0 mg/mL of solution. In another embodiment, the preservative is chlorobutanol and is present in an amount of about 0.5 to 10 mg/mL, preferably in an amount of 2.0 to 8.0 mg/mL of solution. In another embodiment, the preservative is thiomersal and is present in an amount of about 0.01 to 1.5 mg/ml solution, preferably in an amount of 0.05 to 0.5 mg/ml solution. The sterile aqueous solution of octreotide contained in an injection device, such as a pen, remains sterile during use and through the expiration date.

The sterile solution of octreotide or a pharmaceutically acceptable salt thereof contained in the injection device and according to the present invention contains: a higher concentration of octreotide base (2.0 to 2.5 mg/ml) compared to the concentration of the commercially available product , which is the previously known dilute solution (1.0 mg/ml or 0.2 mg/ml octreotide). For example, the administration of a particular dosage requires the injection of a smaller volume of sterile solution compared to the volume of previously known dilute solutions. This, in turn, provides one advantage of the invention, which is a significantly reduced amount of preservative that is administered per dose (per day) compared to prior art octreotide products such as Sandostatin™. For example, a prior art Sandostatin™ octreotide acetate solution containing 1.0 mg/mL octreotide contains X mg/mL preservative. The solution according to the present invention contains octreotide in the range of 2.0 to 2.5 mg/ml and X mg/ml of a preservative to maintain sterility. Thus, when a particular dose of octreotide is administered using the injection device of the present invention, the volume of solution to be administered is 2.0 to 2.5 times lower than prior art dilute solutions and hence the amount of administered preservative is from X/2.0 to X/2.5. This is shown in the table below:

In accordance with one embodiment, the sterile solution contains octreotide in the form of its salt, present at a concentration equivalent to 2.5 mg/ml of octreotide base in a syringe pen, wherein when the injection device delivers 100 μg of octreotide in an injection volume of 40 μl, the amount of preservative administered is 2.5 times less than the amount delivered by subcutaneous injection of 100 μl of a solution containing 1 mg/ml of octreotide base.

According to another embodiment, the sterile solution contains octreotide in the form of its salt at a concentration equivalent to 2.5 mg/ml of octreotide base in a syringe pen, wherein when the injection device delivers 200 μg of octreotide in an injection volume of 80 μl, the amount delivered the preservative is 2.5 times less than the amount delivered by subcutaneous injection of 200 μl of a solution containing 1 mg/ml of octreotide base.

According to another embodiment, the sterile solution contains octreotide in the form of its salt at a concentration equivalent to 2.0 mg/ml octreotide base in an injection device in which when the injection device delivers 100 μg of octreotide in an injection volume of 50 μl, the amount delivered preservative is 2.0 times less than the amount delivered by subcutaneous injection of 100 μl of a solution containing octreotide in the form of its salt, at a concentration equivalent to 1 mg/ml of octreotide base.

In one aspect, the injection device comprises multiple doses of octreotide in the form of a sterile solution thereof, wherein a sterile solution containing octreotide acetate at a concentration equivalent to 2.5 mg/mL of octreotide base and a preservative, where to deliver 100 μg of octreotide, 40 μl of the solution is injected subcutaneously via a pen, and the amount of preservative delivered is 2.5 times less than the amount of preservative delivered by subcutaneous injection of 100 µl of a commercially available solution containing 1 mg/ml octreotide. In another aspect, the injection device comprises multiple doses of octreotide in the form of a sterile solution thereof, the sterile solution containing octreotide acetate at a concentration equivalent to 2.0 mg/mL of octreotide base and a preservative, wherein when the injection device delivers 100 μg of octreotide per the injection volume is 50 μl, the amount of preservative delivered is 2.0 times less than the amount delivered by subcutaneous injection of a solution that contains 1 mg/ml octreotide, and 100 μl of the solution is injected.

In one aspect, the present invention relates to a method of treating diseases selected from acromegaly, carcinoid tumor, vasoactive intestinal peptide tumor, and combinations thereof, in a patient in need thereof, comprising the steps of: subcutaneously administering to said patient a sterile solution containing octreotide acetate present in a concentration, equivalent to 2.0 to 2.5 mg/ml octreotide base, and at least one preservative, in a pharmaceutically acceptable carrier. The sterile solution is contained in an injection device, such as a pen, which is configured to administer 20 to 250 microliters of solution per injection subcutaneously to provide multiple doses of octreotide in an amount ranging from 40 to 625 micrograms per injection. The solution is present in the injection device in volumes of 2.0 to 5.0 ml. In a preferred embodiment, the solution further comprises about 20.0 to about 25.0 mg/ml mannitol and the pH of the solution is in the range of 3.9 to 4.5.

In the context of this description, "comprising" should be interpreted as "including". Aspects of the invention containing certain elements are also intended to be extended to alternative embodiments "consisting" or "consisting essentially" of the corresponding elements. Where technically feasible, embodiments of the invention may be combined.

Embodiments are described herein as containing certain features/elements. The disclosure also extends to individual embodiments consisting or consisting essentially of the indicated features/elements.

In the following, the invention is more specifically described by means of examples. The examples are not intended to limit the scope of the invention and are used by way of illustration only.

Example 1

A sterile solution of octreotide acetate according to one embodiment of the present invention is described below.

Procedure: The specified volume of water for injection was collected in a suitable container at a temperature of 20 to 25°C. To this, octreotide acetate was added with stirring to form a clear solution. The indicated amount of lactic acid was dissolved in the above solution with stirring until a clear solution was obtained. The indicated amount of mannitol was dissolved in the above solution with stirring until a clear solution was obtained. Separately, the phenol was dissolved in the indicated amount of water and added to the above volumetric solution. Additionally, the pH of the solution was adjusted to a value of about 4.20±0.30 with a sufficient amount of sodium bicarbonate solution. This unfiltered bulk solution was stored under a nitrogen atmosphere before being subjected to membrane filtration.

The octreotide acetate bulk solution was sterilized by aseptic filtration through a set of 0.45 micron Nylon 66 capsule filter and 0.2 micron Nylon 66 capsule filter, and the filtered solution was stored under a nitrogen atmosphere. Finally, the indicated volume (2.8 ml) of the solution thus formed was aseptically immersed in a pre-sterilized pen cartridge, and the cartridge was then sealed.

Storage Stability Test The sterile solution of Example 1 contained in the glass cartridge of a multiple dose pen was subjected to stability studies at 2-8°C for 24 months and at 25°C/60% relative humidity (accelerated conditions) in within 6 months. During this storage period, the device was not used, i.e. the solution was not removed and the cartridge was not pierced. It has been analyzed for test and related substances. Phenol analysis was also carried out. The results are shown in Table 2 below.

The results of the above stability tests showed that the solution, which was stored in a multiple dose pen, when stored at 2-8°C for 24 months or at 25°C/60% RH for 6 months, remains stable when In this case, octreotide acetate assay data remains within 95 to 110% label claims and phenol preservative assay data remains within 80 to 120% label claims and associated substances/impurities remain within desired limits. This indicated that the sterile solution of the present invention in the multiple dose pen remained stable during storage throughout the shelf life of the product.

Example 2

An aqueous solution of octreotide acetate having a concentration equivalent to 2.5 mg/mL of octreotide base, filled into a pen according to Example 1 of the present invention, referred to herein as test product A, was subjected to an in vivo pharmacokinetic study in the blood plasma of healthy human volunteers, whereby an administered dose of octreotide acetate solution (equivalent to 100 μg octreotide base) was delivered subcutaneously via a multiple-dose pen to a human volunteer and the plasma pharmacokinetic profile of octreotide was studied. Bioavailability was determined, ie AUC _0-∞ , AUC _0-t , C _max , T _max and other pharmacokinetic parameters. The study was a randomized, open-label, two-treatment, two-period, two-sequence, single-dose, fasting, crossover study in twelve healthy adult human volunteers with a 7-day washout between doses. As a control (C), a commercially available product 1.0 mg/ml Sandostatin™ solution in a multiple dose vial was used, where the same dose, i.e. equivalent to 100 μg octreotide base, was administered to healthy human volunteers using a conventional syringe after withdrawal. from a vial.

Prior to dosing, volunteers abstained from eating at night for 10 hours. Test product A, i.e. 2.5 mg/ml octreotide acetate solution, was injected subcutaneously via a pen after primed and dosed to deliver 40 μl of 2.5 mg/ml sterile octreotide acetate solution corresponding to a dose of 100 μg.

Control (C), i.e. a solution of Sandostatin® octreotide acetate 1.0 mg/mL was administered by first carefully withdrawing 100 μl of the solution from the product vial (corresponding to a dose of 100 μg) by syringe, followed by subcutaneous injection of the solution by the investigator to healthy adult volunteers.

In each of the two study periods, 19 blood samples were collected, including a pre-dose blood sample. A pre-dose 5 ml blood sample was collected within 1 hour prior to the planned dosage. Post-dose blood samples (5 ml each) were drawn at 0.083, 0.167, 0.250, 0.333, 0.500, 0.667, 0.833, 1.000, 1.250, 1.500, 2.000, 3.000, 4.000, 5.000, 6.000, 0.000, and 8.000 hours Plasma octreotide concentration was quantified using an approved LC/MS/MS method (liquid chromatography and tandem mass spectrometry method). The profile of the mean plasma concentration of octreotide (pg/ml) - time after the administration of the test product and the control product was plotted and presented in Figure 1. Pharmacokinetic parameters, namely C _max , T _max , AUC _0-t , AUC _0-∞ , t _1/2 was determined, and the geometric mean values for the test product (A) and control (C) are presented below in table 3.

The average values of C _max, AUC _0-t , AUC _0-∞ for the test product (A) were equivalent to the values of the control (C) and ranged from 85 to 115% of the control (C).

Figure 1 and Table 3 show that the bioavailability of octreotide obtained by subcutaneous administration of an aqueous solution of example 1 (test product A) was equivalent to that obtained by subcutaneous administration of 1.0 mg/ml Sandostatin™ (control C).

Comparative Example 1

Table 4 summarizes a sterile solution of octreotide acetate having a concentration equivalent to 5.0 mg/ml of octreotide base.

The solution was prepared according to the procedure of Example 1.

An aqueous solution of octreotide acetate having a concentration equivalent to 5 mg/mL of octreotide base in the pen according to Comparative Example 1, referred to here as test product B, was subjected to an in vivo plasma pharmacokinetic study in healthy human volunteers, where the administered dose of octreotide acetate solution (equivalent to 100 μg octreotide base) was delivered subcutaneously via a multidose pen and the pharmacokinetic parameters thus observed were compared with those for a control solution, i.e. a commercially available solution of 1.0 mg/ml octreotide Sandostatin™. An open-label, randomized, two-treatment, two-period, two-sequence, single-dose (100 μg octreotide acetate) fasted crossover study was performed in twelve healthy adult volunteers at a dose of 100 μg. They all completed a two-way crossover study. The withdrawal period was 6 days between doses.

An octreotide acetate solution having a concentration equivalent to 5 mg/ml of octreotide base, according to comparative example 1, was administered to healthy human volunteers using a syringe pen in a manner similar to that described in example 2, and studied the pharmacokinetic profile in plasma and determined bioavailability, i.e. e. AUC _0-∞ , C _max and other pharmacokinetic parameters. As a control (C), a commercially available product solution of 1.0 mg/ml Sandostatin™ in a multiple dose vial was used, where the dose was delivered to healthy volunteers using a conventional syringe after withdrawal from the vial.

Prior to dosing, volunteers abstained from eating at night for 10 hours. Test Product B was injected subcutaneously via pen after prime and dose. To deliver a dose of 100 μg, 20 μl of a sterile solution of 5.0 mg/ml octreotide acetate was drawn into the pen to deliver, followed by subcutaneous injection of the solution through the pen.

Control (C), i.e. a solution of 1.0 mg/ml of octreotide acetate was administered by first carefully withdrawing 100 μl of the solution, which corresponded to a dose of 100 μg, from the product tube using a syringe, followed by subcutaneous injection of the solution by the investigator to healthy adult volunteers.

The sampling schedule was similar to Example 2. Plasma octreotide concentration was quantified using a validated LC/MS/MS method (liquid chromatography and tandem mass spectrometry method). The profile of mean plasma octreotide concentration (pg/mL) and time after administration of test product and reference product was plotted and compared (Figure 2). Pharmacokinetic parameters, namely C _max , T _max , AUC _0-t , AUC _0-∞ , t _1/2 were determined, and geometric means for the test product (B) and control (C) are presented below in table 5.

The mean values of C _max , AUC _0-t , AUC _0-∞ for the test product (B) were significantly lower than for the control (C).

It can be seen from Figure 2 and Table 5 that the bioavailability of octreotide observed with subcutaneous administration of an aqueous solution of octreotide having a concentration of 5.0 mg/ml (according to comparative example 1) was only about 5% compared to the control, injection of 1 mg/ml Sandostatin™ and therefore was not bioequivalent.

Surprisingly, blood levels of octreotide, i.e. C _max , AUC _0-t , AUC _0-∞ , were found when the same dose of octreotide was administered subcutaneously by injection of an aqueous solution of octreotide of example 1 (which has a lower concentration of 2.5 mg/ ml) were higher (Fig. 1, Table 3) and comparable with the values for the control group - injection of Sandostatin™ 1.0 mg/ml.

Claims (12)

1. Sterile solution for the treatment of diseases selected from acromegaly, carcinoid tumor, vasoactive intestinal peptide tumor and combinations thereof, containing: octreotide in the form of a pharmaceutically acceptable salt, present at a concentration equivalent to 2.0 to 2.5 mg/ml octreotide base , mannitol at a concentration in the range of 20.0 to 25.0 mg/ml, and phenol, in a pharmaceutically acceptable carrier such as water for injection, wherein the sterile solution is present in the injection device. 2. Sterile solution according to claim 1, wherein the concentration of octreotide base is 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, or 2.5 mg/ml. 3. Sterile solution according to claim 1, in which the concentration of octreotide base is 2.5 mg/ml. 4. The sterile solution according to claim 1, wherein the volume of the solution contained in the injection device is in the range of 2.8 to 3.2 ml. 5. Sterile solution according to claim 1, wherein the solution contains mannitol at a concentration of 22.5 mg/ml. 6. Sterile solution according to claim 1, containing: Ingredients Concentration in mg/ml the base of octreotide in its salt form 2.5 mannitol 22.5 where the pH of the sterile solution is in the range from 3.9 to 4.5. 7. Sterile solution according to any one of paragraphs. 1-6, in which said solution additionally contains lactic acid at a concentration of 3.4 mg/ml. 8. The sterile solution according to claim 1, wherein the injection device is configured to administer from 20 to 250 µl of the sterile solution per injection. 9. A sterile solution according to claim 8, wherein the injection device is configured to administer from 20 to 80 µl of a sterile solution per injection. 10. The sterile solution of claim 1, wherein the injection device is a pen.

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