WO2010039039A1

WO2010039039A1 - Oral formulations of gemcitabine derivatives

Info

Publication number: WO2010039039A1
Application number: PCT/NO2009/000331
Authority: WO
Inventors: Sayeh Ahrabi; Finn Myhren; Ole Henrik Eriksen
Original assignee: Clavis Pharma Asa
Priority date: 2008-10-03
Filing date: 2009-09-23
Publication date: 2010-04-08
Also published as: TW201018470A

Abstract

The present invention relates to oral formulations for certain long chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxycytidine (Gemcitabine). In particular, the present invention relates to a pharmaceutical composition and a method of the preparation thereof, in order to accommodate and enhance the oral absorption of therapeutically effective doses of the said derivatives ameliorating compliance in treatment of cancer.

Description

Oral formulations of gemcitabine derivatives

The present invention relates to a pharmaceutical composition comprising certain long 5 chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxy- cytidine (Gemcitabine) as the active ingredient, hi particular, the present invention relates to a pharmaceutical composition and the method of preparation thereof, suitable for oral administration of therapeutically effective doses of the said derivatives in order to ameliorate compliance in treatment of cancer.

10

Gemcitabine, which is a well known cytostatic compound, marketed under the trade name Gemzar by Eli Lilly & Co., has the formula:

I ₅

Gemzar is administered intravenously (i.v.). The reason for choosing a parenteral administration route is due to the toxicity of gemcitabine. Like a lot of drugs, it obviously would have been desirable to be able to administer gemcitabine orally. Oral administration is usually more acceptable for the patients compared to intravenous 20 administration.

Normally the dose in terms of mg/kg must be increased when administering enterally (orally) compared to parenterally due to bioavailability less than 100%. Therefore, drugs having a high degree of toxicity are not suitable for oral administration.

2₅

This is also the case for gemcitabine. Experiments have shown that the toxicity of gemcitabine is greatly enhanced after oral administration. That is, the toxicity of gemcitabine is largely increased after oral administration compared to the toxicity after intraperitoneal (parenteral) administration. The active ingredients of the pharmaceutical composition of the present invention comprise gemcitabine derivatives of the formula I:

(I)

wherein R₁, R₂ and R₃ are independently selected from hydrogen and Ci₈- and C₂o- saturated and monounsaturated acyl groups, with the proviso that R₁, R₂ and R₃ cannot all be hydrogen.

It is known from WO 98/32762 that the compounds of formula (I) are useful in treatment of cancer.

Moreover, it is known from WO 06/098628 that toxicity after oral administration of derivatives of formula (I) resembles the toxicity of intraperitoneal (parenteral) dosing of gemcitabine as such.

However, formulation of a therapeutically effective amount of the highly lipophilic derivatives of formula (I) into a pharmaceutical composition suitable for oral administration represents a problem. The present invention presents a solution to this problem.

The gemcitabine derivatives of formula (I) have poor aqueous solubility and in silico modelling predicted that the oral absorption of these derivatives most probably would be limited by their solubility rather than their permeability through intestinal cells. This means that in order to increase the extent of absorption and bioavailability, the composition of the excipients in the oral dosage forms should be selected so that the said derivatives were better solubilized.

The above mentioned solubilization strategy by using a careful selection of excipients means that the amount of the active substance, the gemcitabine derivatives of formula (I), in the final dosage will be reduced accordingly. Clearly, with a daily therapeutic dose of several grams, it is essential to find a formulation that can physically and technologically accommodate and solubilize a highest possible content of the active substance in order to reduce the number of the tablets or capsules or other dosage units that the patient needs to take.

Due to the lipophilic character of the said derivatives, lipid-based formulations were investigated. These types of formulations have liquid or semi-solid character meaning that encapsulation of the final composition is necessary. The encapsulation technology based on filling and banding of two-piece hard shell capsules was selected. However, such formulations are also good candidates for filling in soft shell capsules.

Various experiments were performed using different categories of excipients suitable for filling in hard shell capsules. Attempts to increase the amount of the active substance to > 10-15% w/w was mostly unsuccessful, mainly due to a significant increase in the viscosity of the mass both in pure suspensions and in melt solutions. This means that processing of such material for hard shell capsule filling would not be possible.

We have now surprisingly found a formulation and a method of preparation of said formulation, wherein derivatives of formula (I) can be dissolved and processed in a combination of lipid-based excipients in a ratio of at least 1:1. This means that a minimum drug content of 50% w/w of the said derivative in a mixture of the excipients was achievable. The final mass had an appropriate viscosity for capsule filling purposes. The said formulation is a progression of Gattefosse's prior art patent US 6,054, 136B.

In addition, using a dynamic in vitro model of gastrointestinal tract (TEM-I, TNO, The Netherlands), we observed that the capsules disintegrate rapidly and the capsule mass is immediately dispersed in a fine suspension. Surprisingly, this was also the case when several capsules with a total mass of 2500 mg of the active ingredient was tested in the said method, and no precipitation was observed at any time during the 4-5 hour duration of the study. High bioaccessibility of the derivatives of formula (I) and a low level of degradation to gemcitabine was also observed.

Furthermore, we have found that the derivatives of formula (I) after oral administration can perform as excellent prodrugs of gemcitabine.

It is a main objective of the present invention to provide a pharmaceutical composition suitable for oral administration comprising gemcitabine derivatives of formula (I) as the active ingredient, which accommodates and enhances the oral absorption of therapeutically effective doses of the said derivatives, being as efficacious as, or more efficacious than Gemzar, in the treatment of cancer.

This and other objectives of the present invention are achieved by the pharmaceutical composition and method of preparation thereof as described in the attached claims.

According to an embodiment of the present invention a pharmaceutical composition, comprising a gemcitabine derivative of formula I:

(I)

wherein Ri, R₂ and R₃ are independently selected from hydrogen and C₁₈- and C₂₀- saturated and monounsaturated acyl groups, with the proviso that R₁, R₂ and R₃ cannot all be hydrogen, or a pharmaceutically acceptable salt thereof as the active ingredient; wherein the active ingredient is dissolved or dispersed in a lipid-based formulation, comprising a lipophilic phase alone, or in combination with a surfactant and/or a co- surfactant, is provided. Genicitabine has three derivatisable functions, namely the 5'- and 3'-hydroxyl groups and the N^4" amino group. Each group can selectively be transformed into an ester or amide derivative, but di-adducts (di-esters or ester-amides) and tri-adducts may be formed as well. In the case of the di- and tri-adducts the acyl substituent groups need 5 not necessarily be the same.

Currently, the mono-acyl derivatives, i.e. with two of Ri, R₂ and R₃ being hydrogen, are preferred for use as the active ingredient of the present pharmaceutical composition. It is especially preferred that the monosubstitution with the acyl group should be in the 3'-0 io and 5'-0 positions of the sugar moiety, with 5'-0 substitution being most preferred.

The double bond of the mono-unsaturated acyl groups may be in either the cis or the trans configuration, although the therapeutic effect may differ depending on which configuration is used.

I₅

The position of the double bond in the monounsaturated acyl groups also seem to affect the activity. Currently, we prefer to use esters or amides having their unsaturation in the ω-9 position. In the ω-system of nomenclature, the position ω of the double bond of a monounsaturated fatty acid is counted from the terminal methyl group, so that, for0 example, eicosenoic acid (C₂₀: 1 ω-9) has 20 carbon atoms in the chain and a single double bond is formed between carbon 9 and 10 counting from the methyl end of the chain. We prefer to use esters, ester-amides and amides derived from oleic acid (Ci₈: 1 ω-9, cis), elaidic acid (Ci₈: 1 ω-9, trans), eicosenoic acid(s) (C₂₀: 1 ω-9, cis) and (C₂₀: 1 ω-9, trans), and the amides and 5'-esters are currently the most preferred derivatives.5

Esters, ester-amides and amides of gemcitabine derived from stearic acid (Ci₈:0) and eicosanoic acid (C₂₀:0) are advantageously used in some cases.

Elaidic acid (N⁴)-Gemcitabine amide, elaidic acid (5')-gemcitabine ester and elaidic0 acid (3')-gemcitabine ester are among the most preferred derivatives, and according to a preferred embodiment of the invention elaidic acid (5')-gemcitabine ester is the active ingredient of the pharmaceutical composition.

The derivatives of formula (I) are prepared according to methods known in the prior art5 (see WO 98/32762 for further details). The lipophilic phase of the formulation may comprise the following excipients, which function as vehicles and/or bioavailability enhancers: medium chain or long chain triglycerides (e.g. Capmul MCM or Miglyol 812), mono- faty acid esters of glycerol such as glyceryl monolinoleate (e.g. Maisine 35:1) or glyceryl monooleate (e.g. Peceol), fatty acid esters of propylene glycol such as propylene glycol monocaprylate (e.g. Capryol 90) or propylene glycol caprylate (e.g Capryol PGCM), polyglyceryl oleate (e.g. Plurol Oleique CC497) and polyglycolized glycerides (e.g. Labrasol, Gelucire 44/14 or Gelucire 50/13).

In a preferred embodiment of the invention, the lipophilic phase of the pharmaceutical composition is selected from the C8-C18 polyglycolized glycerides with high HLB value of 10-16, preferably lauroyl macro golglycerides or stearoyl macrogolglycerides , more preferably Gelucire 44/14 from Gattefosse.

Furthermore, in an embodiment of the invention, a surfactant with high HLB value of 10-16 is present in the pharmaceutical composition. The surfactant preferably comprises C8-C10 polyglycolized glycerides, more preferred Labrasol from Gattefosse.

In another embodiment of the invention, a co-surfactant is present in the pharmaceutical composition. The co-surfactant has a low HLB value of 3 - 6 and preferably consists of caprylic or lauric esters of propylene glycol, more preferably propylene glycol laurate with the trade name of Lauroglycol FCC from Gattefosse, and still more preferably propylene glycol monolaurate with the trade name Lauroglycol 90 from Gattefosse.

According to a preferred embodiment of the invention the pharmaceutical composition comprises elaidic acid (5')-gemcitabine ester, Gelucire 44/14, Labrasol, and Lauroglycol 90.

Some of the excipients of the pharmaceutical composition are selected to solubilize or to increase the solubility of the compounds of formula (I), or the rate of dispersion or dissolution of the compounds of formula (I) from the formulation in the gastrointestinal environment.

The pharmaceutical composition according to the invention may be in solid, semisolid or liquid form, and may be presented in discrete units such as tablets, capsules or the like, or presented in multi-dosing units. The pharmaceutical form of the composition / may be powder, granules, solution, suspension, emulsion, (nano/micro) self- p emmnullsciiftfyπinngπ, r*r

or

The term "therapeutically effective amount" as used herein refers to from about 0.001 to 10 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutically acceptable salt thereof, more preferred from about 10 mg to 6 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutically acceptable salt thereof, in a formulation containing 0.001 - 100% of the said derivative or salt thereof formulated for oral administration.

The amount of the lipophilic phase may vary from about 1% to 99.99%, preferably 1 - 75%, and more preferably 10 - 60% of the pharmaceutical composition.

The amount of the surfactant may vary from 0 to 90%, preferably 0.1 - 50%, more preferably 5 - 25% of the pharmaceutical composition.

The amount of the co-surfactant may vary from 0 to 90%, preferably 0.1 - 50%, more preferably 1 - 25% of the pharmaceutical composition.

The present invention also provides a process for the preparation of a pharmaceutical composition as mentioned above. The said process comprises the steps of melting all excipients before addition of the active substance in a suitable aliquot of the melt followed by addition of increasing portion of the melt and high shear stirring, or addition of the active substance to any of the melted excipients comprising the lipid- based formulation alone before further dilution of the concentrated mixture with the remainder of the excipients and high-shear stirring.

Alternatively, a pharmaceutical wetting agent may initially be added to the active substance before mixing with the lipid excipients. Examples of the wetting agents are polymers, surfactants, carbohydrates, polysaccharides, mineral solids, oils, alcohols or acids, organic or inorganic.

The final bulk product is kept at a defined temperature so that the molten mass has an optimum viscosity to be prosessed in the capsule- filling machine. The filled capsules are then banded appropriately and allowed to dry. These capsules may be coated with an acid-resistant polymer (enteric coating) to release the active substance in the upper intestine or with other polymers to release the active substance in lower parts of intestine. Examples of such polymers are polymethacrylic acid copolymers or cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethylcellulose, cellulose acetate phthalate or the like.

In another embodiment, the molten mass may be used for preparation of solid formulations through granulation, pelletization, or the like, and encapsulation or tab letting of the final solid particles. In this case, other excipients such as diluents, lubricants, glidants, disintegrants, and/or binding agents may be added.

In the following the invention will be further explained by examples. The examples are only meant to be illustrative and shall not be considered as limiting.

EXAMPLES

EXAMPLE 1

Increasing the amount of elaidic acid (5') gemcitabine ester in solid, semisolid or liquid lipid-based formulations for filling into hard shell capsules.

Formulations were prepared using lipids alone or in combination with other excipients in an attempt to prepare a suitable lipid-based formulation for manufacturing hard shell capsules of elaidic acid (5') gemcitabine ester with high concentration of the active substance.

The following combination of the excipients demonstrated a great ability to dissolve large amounts of elaidic acid (5') gemcitabine ester:

Gelucire 44/14 (75% w/w), Labrasol (20% w/w) and Lauroglycol 90 (5% w/w). The final mass ratio of elaidic acid (5') gemcitabine ester to the total mass was 1 :2 before capsule filling. This means that the final pharmaceutical composition was active substance 50%, Gelucire 44/14 37.5% , Labrasol 10%, Lauroglycol 90 2.5%. The method of manufacturing was by melting the excipients and (high-shear) stirring of the active material, which is suitable for large scale manufacturing.

The above formulation has been placed on ongoing stability studies. So far, excellent stability has been demonstrated up to 12 months after manufacture.

EXAMPLE 2 Bioaccessibility of lipid-based capsules of elaidic acid (5') gemcitabine ester during transit through a validated dynamic model simulating the upper gastrointestinal tract (TIM-I model TNO, The Netherlands)

The formulation of example 1 was investigated in the TEVI-I system simulating the average conditions in the stomach and small intestine of healthy adults during the fasting state (with intake of water on empty stomach) and fed state (with intake of high fat meal, according to the FDA requirements). These conditions include especially the dynamics of gastric emptying and small intestinal transit times, the gastric and the intestinal pH values, and the composition of the oral, gastric and duodenal secretion products (electrolytes, digestive enzymes, bile).

The following three experiments were performed in duplicate:

One capsule containing 250 mg of elaidic acid (5') gemcitabine ester under fasted condition

- Ten capsules each containing 250 mg of elaidic acid (5') gemcitabine ester under fasted condition

Ten capsules each containing 250 mg of elaidic acid (5') gemcitabine ester under fed condition

Using specific filters that remove the solubilised fraction and digested components from the lumen , the filtrate fraction in the jejunum and ileum segment was sampled throughout the study (5-6 hours) and is defined as the bioaccessible fraction of the initial dose (the fraction of the active compound that is potentially available for intestinal absorption in vivo). Also the Ileum effluent containing the non-bioaccessible fraction of the dose was sampled in the same time intervals. All samples were analysed for elaidic acid (5') gemcitabine ester and gemcitabine using HPLC. The capsules released their content within the first 4 minutes after the start of the experiment. During the five hours of the gastrointestinal passage under fasted condition, no precipitation was observed visually in any of the compartments of TIM-I. Under fed condition, this could not be investigated due to the presence of food resulting in opaque character of the fluids.

Figure 1 shows the amount of the bioaccessible elaidic acid (5') gemcitabine ester (as percentage of the initial dose) recovered in the jejunum and ileum filtrate samples per time fraction. The results show that:

- under fasted condition, the bioaccessibility of elaidic acid (5') gemcitabine ester was dose dependent, the higher the dose, the higher the total bioaccessibility. There were no differences between the fed and fasted 5 conditions regarding the total bioaccessibility. the onset of bioaccessibility was immediate in the fasted condition, while a 45 minutes delay was observed in the fed condition.

||_j|The rate of conversion of elaidic acid (5') gemcitabine ester to gemcitabine was low (3-10% during the whole transit time) and the lowest rate occurred io with the higest dose under fasted condition.

EXAMPLE 3

Preliminary PK study of the high-load lipid-based formulation in dogs

I₅

3 male fasted Beagle dogs received one single dose of 15 mg/kg elaidic acid (5') gemcitabine ester. Plasma samples were collected at predefined time intervals. As expected, practically no prodrug (elaidic acid (5') gemcitabine ester) was detected, but a high amount of gemcitabine was observed in plasma. The geometric mean of AUC for 20 gemcitabine was 8160 ng/ml with a coefficient of variance (CV) of onlyl5.3% meaning that there was a low interdog variation in the absorption of gemcitabine. The geometric mean of Tmax was 0.87 h indicating a rapid absorption.

EXAMPLE 4

2₅ Results from ongoing phase I clinical study with the high-load lipid-based capsules of elaidic acid (5') gemcitabine ester

A phase I clinical study using the said capsule formulation is ongoing. The conclusion so far is that the safety profile of the product is of no concern. 21 patients have been 30 enrolled on 6 different dose levels, from 100 mg to 2000 mg in a day 1,8,15 q4w schedule. The most common adverse events were nausea, fatigue, abdominal pain, vomiting and constipation and the majority are of mild intensity. In fact, only a minority of the adverse events are reported as product-related.

3₅ As opposed to gemcitabine, the safety profile of the orally administered elaidic acid (5') gemcitabine ester is similar to that of the intravenousely administered product. In a phase I clinical study with the same schedule as the said oral study, doses up to 1600 mg/m2/day were administered. The dose limiting toxicity was fatigue grade 3. The most frequent toxicities included nausea, fatigue, vomiting and anorexia, the majority of mild intensity (CTCAE grade 1 and 2). The recommended dose (RD) for the intravenous administration in this treatment schedule is 1250 mg/m2 /d.

Claims

C l a i m s

1.

A pharmaceutical composition, comprising 5 a gemcitabine derivative of formula I:

(I)

10

wherein Ri, R₂ and R₃ are independently selected from hydrogen and C]₈- and C₂₀- saturated and monounsaturated acyl groups, with the proviso that R₁, R₂ and R₃ cannot all be hydrogen, or a pharmaceutical acceptable salt thereof as the active ingredient;

I ₅ wherein the active ingredient is dissolved or dispersed in a lipid-based formulation comprising a lipophilic phase, optionally in combination with a surfactant and/or co- surfactant.

2.

20 A pharmaceutical composition according to claim 1, wherein the lipophilic phase is selected from C8-C18 polyglycolized glycerides with high HLB value of 10-16.

3.

A pharmaceutical composition according to any one of claims 1-2, wherein the

2₅ lipophilic phase is lauroyl macrogolglycerides and/or stearoyl macrogolglycerides.

A pharmaceutical composition according to any one of claims 1- 3, wherein the lipophilic phase is Gelucire 44/14.

5.

A pharmaceutical composition according to any one of claims 1-4, wherein the surfactant comprises C8-C10 polyglycolized glycerides.

6.

A pharmaceutical composition according to claim 5, wherein the surfactant comprises

Labrasol.

7.

A pharmaceutical composition according to any one of the preceding claims, wherein the co-surfactant comprises caprylic or lauric esters of propylene glycol.

8. A pharmaceutical composition according to claim 7, wherein the co-surfactant is Lauroglycol 90.

9.

A pharmaceutical composition according to any one of the preceding claims, wherein the active ingredient is elaidic acid (5')-gemcitabine ester.

10.

A pharmaceutical composition according to claim 1, comprising elaidic acid (5')- gemcitabine ester, Gelucire 44/14, Labrasol, and Lauroglycol 90 .

11.

A pharmaceutical composition according to claim 1, wherein the composition is in solid, semisolid or liquid form.

12.

A method of preparation of the pharmaceutical composition according to any one of claims 1-11, comprising the steps of: a) melting the lipophilic phase, optionally together with further excipients; b) adding the active ingredient, and optionally further excepients, to the melt of step a); c) high-shear stirring the melt of step a), optionally the mixture of step b); and d) processing the molten mass obtained in step c) in a capcule-fϊlling machine, or by granulation, or pelletization.