HK1165701B - Self micro-emulsifying oral pharmaceutical composition of hydrophilic drug and preparation method thereof - Google Patents

Abstract

A self-emulsifying oral pharmaceutical composition of hydrophilic drug or its pharmaceutical acceptable salt and the preparation method thereof are disclosed. The composition comprises hydrophilic drug such as bendamustine or gemcitabine, solvent, surfactant and hydrophilic carrier, and has good bioavailability and stability. Said hydrophilic carrier is compatible with drug solution and surfactant.

Description

Self-microemulsifying pharmaceutical compositions of hydrophilic drugs and their preparation

Technical Field

The present invention relates to an oral self-microemulsifying pharmaceutical composition of hydrophilic drugs and a preparation method thereof.

Background

Oral administration (either in solid or liquid suspension form) is a convenient and user-friendly mode of administration, and has been an advantage in the field of drug delivery technology. Even with the acceptable efficiency of oral administration of many types of drugs, there are problems with some classes of drugs, particularly those known to have good solubility but metabolize in large amounts in the liver, be easily excreted by intestinal epithelial cells (poor penetration rate), or irritate the gastric mucosa, such as class III drugs classified in the Biopharmaceutical Classification System (BCS) of the U.S. food and drug administration. Thus, for these drugs, injection administration is the primary option to achieve acceptable drug absorption and bioavailability, however it increases risk and expense and is more painful for the patient.

A new technology, referred to as "self-emulsifying/micro-emulsifying drug delivery system" (SEDDS/SMEDDS), has now been developed which provides a good delivery vehicle that improves the bioavailability of hydrophilic drugs, making oral delivery a viable approach. Generally, SEDDS/SMEDDS is composed of an oil, a surfactant, a co-surfactant or co-solvent, and a hydrophobic drug. The underlying principle of this system is that when SEDDS/SMEDDS is contacted with water, it spontaneously forms an oil-in-water microemulsion under mild mechanical agitation. Thus, the drug may be formulated as a liquid formulation that is soluble in the non-aqueous phase. It can then be subsequently filled into soft/hard gelatin capsules to form solid oral dosage forms. Upon oral administration and contact with gastrointestinal fluids, the oral formulation self-microemulsifies to form microemulsions immediately, thereby facilitating dispersion, dissolution, stabilization and absorption of the drug, and thus improving the bioavailability of the drug. However, there are many limitations to making hydrophilic drugs suitable for their presence within SEDDS/SMEDDS. Other strategies, such as liposomes, microparticles, or prodrugs, are known to increase the bioavailability of hydrophilic drugs, as described, for example, in U.S. patent nos. 7,220,428, 7,053,076, 7,217,735, and 7,309,696, and PCT publication nos. WO2004/017944 and WO 2007/089043.

Therefore, there is still a need to develop an oral dosage form of hydrophilic drugs, especially an oral self-microemulsifying pharmaceutical composition with good bioavailability and stability.

Disclosure of Invention

In one aspect, the present invention provides an oral self-microemulsifying pharmaceutical composition comprising:

(a) a therapeutically effective amount of a hydrophilic drug or a pharmaceutically acceptable salt thereof;

(b) one or more solvents that can dissolve the hydrophilic drug or pharmaceutically acceptable salt thereof to form a drug solvent solution;

(c) a surfactant system comprising one or more surfactants, the surfactant system having a hydrophilic-lipophilic balance (HLB) value of from about 8 to about 17; and

(d) one or more hydrophilic carriers compatible with the drug solvent solution and the surfactant system;

wherein the pharmaceutical composition is in the form of a self-microemulsifying formulation for oral administration.

In another aspect, the present invention provides a method for preparing the aforementioned oral self-microemulsifying pharmaceutical composition, which comprises mixing the hydrophilic drug or its pharmaceutically acceptable salt with the one or more solvents, the one or more hydrophilic carriers and the surfactant system to form the oral self-microemulsifying pharmaceutical composition.

Various embodiments of the invention are described in detail below. Other features of the present invention will be apparent from the following detailed description and drawings of the various embodiments, and from the claims.

Without further elaboration, it is believed that one skilled in the art can, using the description herein, utilize the present invention to its fullest extent. The following description is, therefore, to be regarded as illustrative only and not in any way limiting the scope of the invention.

Drawings

For the purpose of illustrating the invention, there is shown in the drawings embodiments which are presently preferred. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described.

Figure 1 is a graph of plasma concentration of gemcitabine following intravenous and oral administration.

FIG. 2 is a graph of plasma concentrations of 2 ', 2' -difluorodeoxyuracil (dFdU) after intravenous and oral administration.

Detailed Description

Unless defined otherwise herein, the scientific and technical terms used in connection with the present invention have the same meaning as commonly understood by one of ordinary skill in the art. As used herein, the following terms have their intended meanings unless otherwise indicated.

Unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

The present invention provides an oral self-microemulsifying pharmaceutical composition of a hydrophilic drug, which comprises, in addition to the hydrophilic drug, one or more solvents that can dissolve the hydrophilic drug to produce a drug solvent solution, and a surfactant system comprising one or more surfactants having an HLB value of about 8 to about 17, one or more hydrophilic carriers that are compatible with the drug solvent solution and the surfactant system. The oral self-microemulsifying pharmaceutical composition of the present invention has excellent bioavailability equivalent to that of intravenous injection when administered orally.

Accordingly, in one aspect, the present invention provides an oral self-microemulsifying pharmaceutical composition comprising:

(a) a therapeutically effective amount of a hydrophilic drug or a pharmaceutically acceptable salt thereof;

(b) one or more solvents that can dissolve the hydrophilic drug or pharmaceutically acceptable salt thereof to form a drug solvent solution;

(c) a surfactant system comprising one or more surfactants, the surfactant system having a hydrophilic-lipophilic balance (HLB) value of from about 8 to about 17; and

(d) one or more hydrophilic carriers compatible with the drug solvent solution and the surfactant system;

wherein the pharmaceutical composition is in the form of a self-microemulsifying formulation for oral administration.

The term "self-microemulsifying" as used herein describes that when the formulation contacts a water-soluble base (e.g., is mixed with water) a fine oil-water emulsion is produced. In particular, the self-microemulsifying pharmaceutical compositions of the present invention, when contacted with a water-soluble base, form emulsions having an average particle size of less than about 800nm, more particularly less than about 400nm, even more particularly less than about 200nm, and most particularly less than about 100 nm. In one embodiment, the self-microemulsifying pharmaceutical composition of the present invention, when contacted with an aqueous base, forms an emulsion having an average particle size of less than about 10 nm.

The term "therapeutically effective amount" as used herein refers to an amount of a drug effective to produce a therapeutic effect, and particularly to an amount of a drug that produces a therapeutic effect on a target organ in the blood after the drug is absorbed into the body through the Gastrointestinal (GI) tract wall. Those skilled in the art will appreciate that the amount of drug present in the composition will vary depending on the particular circumstances, including but not limited to, for example, the type and dosage form of the drug and the weight, age and health of the organism.

In accordance with the present invention, the term "pharmaceutically acceptable salt" as used herein includes, but is not limited to, acid addition salts which substantially retain the biological effectiveness and properties of the free base. Such acid addition salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as acetic acid, propionic acid, pyruvic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, trifluoroacetic acid, and the like.

According to the present invention, a hydrophilic drug refers to a drug having a degree of solubility in a water-soluble matrix relative to a lipophilic drug. In particular, the hydrophilic drugs used in the present invention have high solubility as defined by BCS, i.e., the highest dose is soluble in 250ml or less of water at a pH ranging from 1 to 7.5. Examples of hydrophilic drugs include, but are not limited to, aminoalcohol (albuterol), bendamustine (bendamustine), captopril (captopril), carboplatin (carboplatin), ciprofloxacin (ciprofloxacin), gemcitabine (gemcitabine), ibandronate (ibandronate), lamivudine (lamivudine), nicotinic acid (niacin), oxycodone (oxycodone), ranitidine (ranitidine), and sumatriptan (sumatriptan). In some embodiments of the invention, the hydrophilic drug is bendamustine or gemcitabine. In a particular embodiment, the hydrophilic drug is present in an amount ranging from about 0.2% to about 15% (w/w), based on the weight of the pharmaceutical composition.

According to the present invention, the one or more solvents herein can dissolve the hydrophilic drug or a pharmaceutically acceptable salt thereof to form a drug solvent solution. In particular, each of the one or more solvents may dissolve about 1 part of the hydrophilic drug or a pharmaceutically acceptable salt thereof in less than about 100 parts of the solvent. More particularly, the one or more solvents are selected from the group consisting of: (a) a first solvent that can dissolve about 1 part of a hydrophilic drug or a pharmaceutically acceptable salt thereof in less than about 1 part of the first solvent (very soluble), (b) a second solvent that can dissolve about 1 part of the hydrophilic drug or a pharmaceutically acceptable salt thereof in about 1 to about 10 parts of the second solvent (very soluble), (c) a third solvent that can dissolve about 1 part of the hydrophilic drug or a pharmaceutically acceptable salt thereof in about 10 to about 30 parts of the third solvent (soluble), (d) a fourth solvent that can dissolve about 1 part of the hydrophilic drug or a pharmaceutically acceptable salt thereof in about 30 to about 100 parts of the fourth solvent (sparingly soluble), and (e) any combination thereof. Generally, an approximate volume of solvent corresponds to one part by weight of solute. For example, the first solvent may dissolve about 1g of the hydrophilic drug in less than 1ml of the solvent. Examples of solvents herein include, but are not limited to, water, ethanol, polyethylene glycol (PEG), isopropyl alcohol (IPA), 1, 2-propanediol (propylene glycol, PG), glycerol, and acetic acid. Any of the above solvents may be used alone, or in combination. In one embodiment, the self-microemulsifying pharmaceutical composition of the present invention comprises water as a solvent. In a particular embodiment, the aforementioned one or more solvents are present in an amount ranging from about 2.5% to about 60% (w/w), based on the weight of the pharmaceutical composition.

According to the present invention, the surfactant system herein comprises one or more surfactants, the surfactant system having an HLB value of from about 8 to about 17. In the art, the HLB value is known to be based on the average between the hydrophilic and lipophilic portions of the surfactantBalance to determine the type of surfactant; a higher HLB value refers to a surfactant with stronger hydrophilicity; while a lower HLB value refers to a less hydrophilic surfactant. According to the present invention, a single surfactant having an HLB value of about 8 to about 17 may be used. Alternatively, a combination of a higher HLB surfactant and a lower HLB surfactant may be used, with the resulting mixed surfactant being present in a ratio such that the mixed surfactant exhibits an HLB value in the range of from about 8 to about 17. The one or more surfactants useful in the present invention can be cationic surfactants, anionic surfactants, or nonionic surfactants. Examples of surfactants include, but are not limited to, polysorbates, poloxamers, oleoyl polyoxylglycerides (oleoyl polyoxylglycerides, such as Labrafil M1944 CS), linoleoyl polyoxylglycerides (linoleoyl polyoxylglycerides, such as Labrafil M2125 CS), caprylocaproyl polyoxylglycerides (caprylocaproyl polyoxylglycerides, such as Labol), polyoxyethylene castor oil derivatives (polyoxyethylene castor oil derivatives, such as PEG40 hydrogenated castor oil, Cremophor EL or Cremophor RH), polyoxyethylene alkyl ethers (oxyethylene alkyl ethers, such as Brij), sorbitan fatty acid esters (polyoxyethylene fatty acids, such as Spans), monoglycerides (glyceryl monooleates, such as polyethylene glycol monooleates, such as Brij), glyceryl monooleate esters (glyceryl monostearate, such as glyceryl monostearate), and the like) Glycerol monolinoleate (e.g. glycerol monolinoleate)35-1), Medium Chain Triglycerides (MCT), polyglycerol esters (e.g., such asOleique CC 497), lauryl polyoxylglyceride (lauroyl polyoxylglyceride, e.g., as44/14）、Stearoyl polyoxylglycerides (stearoyl polyoxylglycerides, e.g. stearyl polyoxylglycerides, or stearyl polyoxylglycerides)50/13), propylene glycol dioctyl sebacate (propylene glycol dioctyl phthalate, e.g. propylene glycol dioctyl phthalatePG), propylene glycol laurate (propylene glycol laurate, e.g. propylene glycol laurate (PG)FCC), propylene glycol monolaurate (propylene glycol monolaurate, e.g., ethylene glycol monolaurate, propylene glycol monolaurate, and propylene glycol monolaurate90) Propylene glycol caprylate (propylene glycol caprylate, such as Capryol PGMC), and propylene glycol monocaprylate (propylene glycol monocaprylate, such as Capryol 90). Any of the above surfactants may be used alone, or a plurality of surfactants may be used in combination. Preferably, the present invention may use a single surfactant or a combination of surfactants having an HLB value of from about 8 to about 17, more preferably from about 10 to about 12. In an embodiment, the self-microemulsifying pharmaceutical composition of the present invention comprises polysorbate and oleoyl polyoxylglyceride as the surfactant system. In a particular embodiment, the surfactant system is present in an amount ranging from about 20% to about 75% (w/w), based on the weight of the pharmaceutical composition.

According to the present invention, one or more hydrophilic carriers are compatible with the above-described drug solvent solution (consisting of a hydrophilic drug and a solvent) and surfactant system. By "compatible" herein is meant that the one or more hydrophilic carriers can be mixed with, or dispersed in, the above-described drug solvent solution and the surfactant system to form a stable homogeneous solution. In particular, each of the one or more hydrophilic carriers can dissolve about 1 part of the hydrophilic drug or a pharmaceutically acceptable salt thereof in about 10 to about 10,000 parts of the hydrophilic carrier.More particularly, the one or more solvents are selected from the group consisting of: (a) a first hydrophilic carrier that can dissolve about 1 part of a hydrophilic drug or a pharmaceutically acceptable salt thereof in about 10 to about 30 parts of the first hydrophilic carrier (soluble), (b) a second hydrophilic carrier that can dissolve about 1 part of a hydrophilic drug or a pharmaceutically acceptable salt thereof in about 30 to about 100 parts of the second hydrophilic carrier (sparingly soluble), (c) a third hydrophilic carrier that can dissolve about 1 part of a hydrophilic drug or a pharmaceutically acceptable salt thereof in about 100 to about 1,000 parts of the third hydrophilic carrier (sparingly soluble), (d) a fourth hydrophilic carrier that can dissolve about 1 part of a hydrophilic drug or a pharmaceutically acceptable salt thereof in about 1,000 to about 10,000 parts of the fourth hydrophilic carrier (very sparingly soluble), and (e) any combination thereof. Examples of hydrophilic carriers include, but are not limited to, polysorbates, ethanol, polyethylene glycols (PEG, e.g., PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG3000, PEG4000, PEG6000, or PEG 8000), glycerol, 1, 2-Propanediol (PG), Propylene Carbonate (PC), and diethylene glycol monoethyl ether (e.g., Propylene Carbonate (PC)), and diethylene glycol monoethyl etherHP). Any of the above hydrophilic carriers can be used alone, or a plurality of hydrophilic carriers can be used in combination. In a particular embodiment, the one or more hydrophilic carriers are present in an amount ranging from about 2% to about 60% (w/w), based on the weight of the pharmaceutical composition.

Moreover, in some examples, it is particularly advantageous to use a combination of a particular solvent and a hydrophilic vehicle, e.g., (i) a combination of a first solvent and a second, third, or fourth hydrophilic vehicle; (ii) a combination of a second solvent and a second or third hydrophilic carrier; (iii) a third solvent in combination with a second or third hydrophilic carrier; and (i) a combination of a fourth solvent and the first, second, or third hydrophilic vehicle. The solvent and the hydrophilic carrier are present together in an amount ranging from about 25% to about 65% (w/w), more specifically from about 40% to about 60% (w/w), and still more specifically about 50% (w/w), based on the weight of the pharmaceutical composition of the present invention. Still more particularly, the solvent and hydrophilic carrier are present in a ratio of about 1:0.1 to about 1:9 (by weight in the pharmaceutical composition of the invention). More particularly, if the pharmaceutical composition of the invention is in the form of an oral solution, the solvent and hydrophilic drug are present in a ratio of about 1:0.1 to about 1:2 (based on the weight in the pharmaceutical composition of the invention), and if the pharmaceutical composition of the invention is in the form of a capsule, the solvent and hydrophilic carrier are present in a ratio of about 1:1 to about 1:9 (based on the weight in the pharmaceutical composition of the invention). In another aspect, the hydrophilic carrier and the surfactant system are present together in an amount ranging from about 50% to about 95% (w/w), more specifically from about 65% to about 85% (w/w), and even more specifically about 75% (w/w), based on the weight of the pharmaceutical composition of the invention. Still more particularly, the hydrophilic carrier and surfactant system are present in a ratio of from about 1:0.3 to about 1:32.5, still more particularly from about 1:1 to about 1:20, and still more particularly about 1:1.5 (by weight in the pharmaceutical composition of the invention).

In one embodiment, the solvent, hydrophilic carrier, and surfactant system are present in a ratio of about 2:3: 4.5.

In addition, the self-microemulsifying pharmaceutical composition of the present invention may optionally include other ingredients, including antioxidants, for example, antioxidants such as D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS).

In a specific embodiment, the self-microemulsifying pharmaceutical composition of the present invention comprises gemcitabine or a pharmaceutically acceptable salt thereof, water, glycerin, PEG, polysorbate, and oleoyl polyoxylglyceride. In a specific example, gemcitabine is present in an amount of about 2.00% (w/w) based on the weight of the pharmaceutical composition, water is present in an amount of about 20.00% (w/w) based on the weight of the pharmaceutical composition, glycerol and PEG are present together in an amount of about 32.30% (w/w) based on the weight of the pharmaceutical composition, and polysorbate and oleoyl polyoxylglyceride are present together in an amount of about 45.70% (w/w) based on the weight of the pharmaceutical composition.

In a specific embodiment, the self-microemulsifying pharmaceutical composition of the present invention comprises gemcitabine or a pharmaceutically acceptable salt thereof, water, 1, 2-propanediol, PEG, polysorbate, and oleoyl polyoxylglyceride. In a specific example, gemcitabine is present in an amount of about 2.00% (w/w) based on the weight of the pharmaceutical composition, water is present in an amount of about 20.00% (w/w) based on the weight of the pharmaceutical composition, 1, 2-propanediol and PEG are present together in an amount of about 32.30% (w/w) based on the weight of the pharmaceutical composition, and polysorbate and oleoyl polyoxylglyceride are present together in an amount of about 45.70% (w/w) based on the weight of the pharmaceutical composition.

In a specific embodiment, the self-microemulsifying pharmaceutical composition of the present invention comprises gemcitabine or a pharmaceutically acceptable salt thereof, water, glycerin, PEG, polysorbate, oleoyl polyoxylglyceride, and TPGS. In a specific example, gemcitabine is present in an amount of about 1.98% (w/w) based on the weight of the pharmaceutical composition, water is present in an amount of about 19.8% (w/w) based on the weight of the pharmaceutical composition, glycerol and PEG are present together in an amount of about 31.98% (w/w) based on the weight of the pharmaceutical composition, polysorbate and oleoyl polyoxylglyceride are present together in an amount of about 45.25% (w/w) based on the weight of the pharmaceutical composition, and TPGS is present together in an amount of about 0.99% (w/w) based on the weight of the pharmaceutical composition.

In addition, the self-microemulsifying pharmaceutical composition of the present invention may be optionally adjusted to exhibit a pH higher than the dissociation coefficient (pKa) of the contained hydrophilic drug, so as to increase the stability of drug storage. In one embodiment, the pH of the self-microemulsifying pharmaceutical composition containing gemcitabine of the present invention is further adjusted to be higher than 4.0, for example, between 4 and 5, between 5 and 6, between 6 and 7, or between 7 and 8.

The self-microemulsifying pharmaceutical composition according to the present invention has excellent bioavailability equivalent to that of a drug injected intravenously when the drug is administered orally. In a specific example, the bioavailability of the self-microemulsifying pharmaceutical composition of the present invention by oral administration is about 89%, which is compared to the conventional formulation in injection form (see example 4 below).

The self-microemulsifying pharmaceutical composition of the present invention has good stability, specifically, it does not substantially undergo phase separation, precipitation of components, change in texture, or degradation of active ingredients contained therein during a period of storage. By "without substantial degradation of the active ingredient contained therein" is meant that the amount of degradation of the active ingredient contained in the pharmaceutical composition of the present invention after storage for a period of time is less than 20%, preferably less than 10%, more preferably less than about 5% of the amount of active ingredient contained in the original pharmaceutical composition.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, powders, or coated granules, which may contain pharmaceutical excipients known in the art, such as, optionally, binders, fillers, filling/binding agents, adsorbents, wetting agents, disintegrants, lubricants, and the like.

In certain embodiments of the invention, the pharmaceutical composition is enclosed in a sealed soft or hard capsule. The capsule typically dissolves in a specific region of the gastrointestinal tract releasing its contents. Examples of such capsules are enteric-coated soft or hard gelatin capsules. Enteric coating as it is meant is coating with a substance or combination of substances that is insoluble in gastric juice but can decompose in the small intestine.

The self-microemulsifying pharmaceutical compositions of the present invention may be prepared by mixing the aforementioned hydrophilic drug or pharmaceutically acceptable salt thereof with the aforementioned one or more solvents, the aforementioned one or more hydrophilic carriers, and the aforementioned one or more surfactants using standard methods commonly used in the art based on the present disclosure. In some embodiments, the hydrophilic drug is first mixed with the one or more solvents and the one or more hydrophilic carriers, and then mixed with the one or more surfactants. Details of the preparation method are illustrated in the following examples.

The present invention will now be described more specifically with reference to the following specific examples, which are intended for purposes of illustration and not limitation.

Example 1: preparation of self-microemulsifying pharmaceutical composition

1. Formulation I

Gemcitabine hydrochloride (100 mg) was added to distilled water (1,000 mg), glycerol (105 mg), and PEG400 (1,510 mg), followed by stirring until complete dissolution, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring the solution A into the solution B, then stirring until a clear solution is obtained to generate a formulation I, and further preparing the formulation I into hard or soft capsules by using a conventional method.

Table 1 shows the composition of formulation I

2. Formulation II

Gemcitabine hydrochloride (100 mg) was added to distilled water (1,000 mg), 1, 2-propanediol (105 mg), and PEG400 (1,510 mg), followed by stirring until complete dissolution, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring the solution A into the solution B, then stirring until a clear solution is obtained to generate a formulation II, and further preparing the formulation II into hard or soft capsules by using a conventional method.

Table 2 shows the composition of formulation II

3. Formulation III

Gemcitabine hydrochloride (100 mg) was added to distilled water (1,000 mg), glycerol (105 mg), PEG400 (1,510 mg), and TPGS (50 mg), followed by agitation until completely dissolved, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring the solution A into the solution B, then stirring until a clear solution is obtained to generate a formulation III, and further preparing the formulation III into hard or soft capsules by using a conventional method.

Table 3 shows the composition of formulation III

4. Formulation IV

Gemcitabine hydrochloride (100 mg) was added to distilled water (901.3 mg), 4.0N sodium hydroxide solution (98.7 mg), glycerin (105 mg), and PEG400 (1,510 mg), followed by stirring until complete dissolution, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring the solution A into the solution B, then stirring until a clear solution is obtained to generate a formulation IV, and further preparing the formulation IV into hard or soft capsules by using a conventional method.

Table 4 shows the composition of formulation IV

5. Formulation V

Gemcitabine hydrochloride (100 mg) was added to distilled water (901.3 mg), 4.0N sodium hydroxide solution (98.7 mg), 1, 2-propanediol (105 mg), PEG400 (1,510 mg), and TPGS (50 mg), followed by agitation until completely dissolved, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring the solution A into the solution B, then stirring until a clear solution is obtained to generate a formulation V, and further preparing the formulation V into hard or soft capsules by using a conventional method.

Table 5 shows the composition of formulation V

6. Formulation VI

Gemcitabine hydrochloride (100 mg) was added to distilled water (913.28 mg), 4.0N sodium hydroxide solution (86.72 mg), glycerol (105 mg), and PEG400 (1,510 mg), followed by stirring until completely dissolved, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring solution A into solution B, then stirring until a clear solution is obtained, producing formulation VI, which is further processed into hard or soft capsules using known methods.

Table 6 shows the composition of formulation VI

7. Formulation VII

Gemcitabine hydrochloride (100 mg) was added to distilled water (720.21 mg), 4.0N sodium hydroxide solution (279.79 mg), glycerol (105 mg), and PEG400 (1,510 mg), followed by stirring until completely dissolved, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring the solution A into the solution B, stirring until a clear solution is obtained to generate a formulation VII, and further preparing the formulation VII into hard or soft capsules by using a conventional method.

Table 7 shows the composition of formulation VII

8. Formulation VIII

Gemcitabine hydrochloride (100 mg) was added to distilled water (715 mg), 4.0N sodium hydroxide solution (285 mg), glycerol (105 mg), and PEG400 (1,510 mg), followed by agitation until completely dissolved, yielding solution A. In another vessel, Tween80 (1,613 mg) and Labrafil M1944CS (672 mg) were mixed homogeneously to give solution B. Pouring the solution A into the solution B, then stirring until a clear solution is obtained to generate a formulation VIII, and further preparing the formulation VIII into hard or soft capsules by using a conventional method.

Table 8 shows the composition of formulation VIII

Example 2: particle size measurement of self-microemulsifying pharmaceutical composition of the present invention

The particle size of the droplets of the microemulsion of formulation I was measured. Briefly, 250mg of distilled water was poured into a small dissolution flask and then heated to 37 ℃. When the temperature reached 37 ℃, 0.25ml of formulation I to be tested was added to the bottle. The mixture was stirred for 10 minutes using a stirring paddle at 100 rpm. After 10 minutes, about 1ml of the mixture was transferred to a sample tube and the particle size of the droplets of the microemulsion was measured by a Zetasizer particle sizer (Zetasizer Nano-ZS; Malvern instruments, UK) according to the instructions of the manufacturer's manual. Table 9 shows the particle size of the droplets of the microemulsion formed by the pharmaceutical composition of the present invention.

TABLE 9

Example 3: preparation of comparative formulations

First, gemcitabine hydrochloride (53 mg) was added to distilled water (4,947 mg), and the solution was stirred until gemcitabine was completely dissolved, yielding a comparative formulation (5,000 mg).

Table 10 comparative formulation compositions

Example 4: biological analysis

The formulation prepared in example 1 (1 mg/kg) was administered via nasogastric tubing to beagle dogs; and the comparative formulation prepared in example 2 (1 mg/kg) was administered to another beagle dog by intravenous injection. Blood was collected from dogs at 5, 10, 15, 30 and 45 minutes, and 1,2, 4, 8 and 12 hours post-dose, respectively. The collected blood is put into a test tube containing a reaction terminator and an anticoagulant, and the mixture is continuously centrifuged to obtain plasma. Gexitabine and its major metabolites were analyzed by LC/MS (liquid chromatography/mass spectrometer). The results of the bioanalysis are shown in FIGS. 1 and 2 and tables 11 and 12.

Table 11: chamber-free model analysis of pharmacokinetic parameters of gemcitabine in plasma

Table 12: chamber-free model analysis of pharmacokinetic parameters of dFdU in plasma

According to the above results, it was found that gemcitabine can be absorbed well by oral administration by the self-microemulsifying pharmaceutical composition of the present invention. The relative bioavailability of the self-microemulsifying pharmaceutical composition of the present invention is about 89% (3.22/3.60) compared to the comparative formulation via intravenous injection. Furthermore, the plasma dFdU curves of the self-microemulsifying pharmaceutical compositions of the present invention and the comparative formulations are similar, indicating a lower first-pass metabolism effect (first-pass metabolic effects) compared to the oral formulation of gemcitabine in the prior art. The present invention proposes for the first time novel oral gexitabine self-microemulsifying pharmaceutical compositions with excellent bioavailability equivalent to intravenous formulations used in the art.

Example 5: analysis of stability

The stability analyses for formulations I to VIII of the foregoing example 1 can be performed according to methods known in the art. Briefly, approximately 2g of the formulation was added to a 4ml tube, filled with liquid nitrogen, and sealed with a teflon gasket and an aluminum cap. The sealed test tube is placed in a constant temperature and humidity chamber (25 ℃ and 60% relative humidity; or 40 ℃ and 75% relative humidity) for at least 30 days. At a specific time point, a portion of the tube was removed and the sample was poured into a 100ml measuring vial. The residual sample was diluted with distilled water and collected into the same measuring flask, and finally the volume was made up to 100ml with water. HPLC analysis was performed to determine the content (w) of gemcitabine in the samples collected in the measuring flasks. The degradation rate (%) of gemcitabine was calculated as follows:

table 13 shows the degradation rate results for formulations I to VIII of the present invention.

Condition 1 is 25 ℃ and 60% relative humidity; condition 2 is 40 ℃ and 75% relative humidity; ND is not determined.

According to the results, the inventive formulations I to VIII can maintain high stability at room temperature 25 ℃ for at least 30 days (degradation rate below 10%), while the formulations IV to VIII (pH above 4) can maintain high stability at high temperature 40 ℃ for at least 30 days (degradation rate below 10%).

All of the features disclosed in this patent specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. From the foregoing description, one skilled in the art can make various changes and modifications to the invention to adapt it to various usages and conditions without departing from the spirit and scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed, but that the invention will include all modifications encompassed within the scope of the appended claims.

Claims (10)

1. An oral self-microemulsifying pharmaceutical composition comprising:

(a) a therapeutically effective amount of gemcitabine or a pharmaceutically acceptable salt thereof;

(b) one or more solvents that can dissolve the hydrophilic drug or pharmaceutically acceptable salt thereof to form a drug solvent solution, wherein each of the one or more solvents can dissolve 1 part of the hydrophilic drug or pharmaceutically acceptable salt thereof in less than 100 parts of the solvent;

(c) a surfactant system comprising one or more surfactants, the surfactant system having a hydrophilic-lipophilic balance (HLB) value of from 8 to 17; and

(d) one or more hydrophilic carriers compatible with the drug solvent solution and the surfactant system, wherein each of the one or more hydrophilic carriers can dissolve 1 part of a hydrophilic drug or a pharmaceutically acceptable salt thereof in 10 to 10,000 parts of the hydrophilic carrier;

wherein the content of the component (a) is 0.2 to 15% (w/w), the content of the component (b) is 2.5 to 60% (w/w), the content of the component (c) is 20 to 75% (w/w), and the content of the component (d) is 2 to 60% (w/w), based on the total weight of the pharmaceutical composition, and the content range in which the component (b) and the component (d) are present together is 25 to 65% (w/w), and the content range in which the component (c) and the component (d) are present together is 50 to 95% (w/w);

using water, glycerol or 1, 2-propanediol and polyethylene glycol (PEG) as solvents or glycerol or 1, 2-propanediol and polyethylene glycol (PEG) as hydrophilic carriers, and polysorbate and oleoyl polyoxylglycerides as surfactants; and

the gemcitabine or a pharmaceutically acceptable salt thereof is first mixed with the one or more solvents and the one or more hydrophilic carriers and then mixed with the surfactant system to form a self-microemulsifying formulation for oral administration.

2. An oral self-microemulsifying pharmaceutical composition according to claim 1, wherein when the pharmaceutical composition contacts an aqueous base an emulsion having a particle size of less than 800nm is formed.

3. An oral self-microemulsifying pharmaceutical composition according to claim 1, which comprises glycerol and PEG as hydrophilic carriers.

4. An oral self-microemulsifying pharmaceutical composition according to claim 1, which comprises 1, 2-propanediol and PEG as hydrophilic carriers.

5. An oral self-microemulsifying pharmaceutical composition according to claim 3, which has a pH greater than 4.0.

6. An oral self-microemulsifying pharmaceutical composition according to claim 1, which comprises gemcitabine or a pharmaceutically acceptable salt thereof, water, glycerin, PEG, polysorbates and oleoyl polyoxylglycerides.

7. An oral self-microemulsifying pharmaceutical composition according to claim 1, which comprises gemcitabine or a pharmaceutically acceptable salt thereof, water, 1, 2-propanediol, PEG, polysorbate and oleoyl polyoxylglyceride.

8. An oral self-microemulsifying pharmaceutical composition according to claim 1, which comprises gemcitabine or a pharmaceutically acceptable salt thereof, water, glycerin, PEG, polysorbates, oleoyl polyoxylglycerides and D- α -tocopheryl polyethylene glycol 1000 succinate (TPGS).

9. An oral self-microemulsifying pharmaceutical composition selected from the group consisting of:

(i) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 2.00% (w/w) gemcitabine hydrochloride, 20.00% (w/w) water, 2.10% (w/w) glycerol, 30.20% (w/w) PEG400, 32.30% (w/w) Tween80 and 13.40% (w/w) Labrafil M1944CS, wherein gemcitabine hydrochloride is added to water, glycerol and PEG400, then stirred until completely dissolved to form solution a, Tween80 and Labrafil 1944CS are uniformly mixed to form solution B, and then the oral self-microemulsifying pharmaceutical composition is formed by pouring solution a into solution B and stirring and mixing;

(ii) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 2.00% (w/w) gemcitabine hydrochloride, 20.00% (w/w) water, 2.10% (w/w) 1, 2-propanediol, 30.20% (w/w) PEG400, 32.30% (w/w) Tween80, and 13.40% (w/w) Labrafil M1944CS, wherein gemcitabine hydrochloride is first added to water, 1, 2-propanediol, and PEG400, then stirred until completely dissolved to form solution a, Tween80 and Labrafil M1944CS are uniformly mixed to form solution B, and then the oral self-microemulsifying pharmaceutical composition is formed by pouring solution a into solution B and stirring and mixing;

(iii) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 1.98% (w/w) gemcitabine hydrochloride, 19.80% (w/w) water, 2.08% (w/w) glycerol, 29.90% (w/w) PEG400, 0.99% (w/w) TPGS, 31.94% (w/w) Tween80, and 13.31% (w/w) Labrafil M1944CS, wherein gemcitabine hydrochloride is first added to water, glycerol, PEG400, and TPGS, then stirred until completely dissolved to form solution a, Tween80 and Labrafil M1944CS are uniformly mixed to form solution B, and then the oral microemulsion pharmaceutical composition is formed by pouring solution a into solution B and stirring and mixing;

(iv) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 2.00% (w/w) gemcitabine hydrochloride, 18.03% (w/w) water, 1.97% (w/w) 4.0N NaOH, 2.10% (w/w) glycerol, 30.20% (w/w) PEG400, 32.30% (w/w) Tween80, and 13.40% (w/w) Labrafil M1944CS, wherein gemcitabine hydrochloride is first added to water, NaOH, glycerol, and PEG400, then stirred until completely dissolved to form solution a, Tween80 is then mixed uniformly with Labrafil M1944CS to form solution B, and then mixed by pouring solution a into solution B to form the oral self-microemulsifying pharmaceutical composition;

(v) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 1.98% (w/w) gemcitabine hydrochloride, 17.85% (w/w) water, 1.95% (w/w) 4.0N NaOH, 2.08% (w/w) 1, 2-propanediol, 29.90% (w/w) PEG400, 0.99% (w/w) TPGS, 31.94% (w/w) Tween80, and 13.31% (w/w) labrafil m1944CS, wherein gemcitabine hydrochloride is first added to water, NaOH, 1, 2-propanediol, PEG400, and TPGS, then stirred until completely dissolved to form solution a, Tween80 is then uniformly mixed with labrafil m1944CS to form solution B, and the oral self-microemulsifying pharmaceutical composition is formed by pouring solution a into solution B and mixing;

(vi) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 1.98% (w/w) gemcitabine hydrochloride, 18.26% (w/w) water, 1.74% (w/w) 4.0N NaOH, 2.10% (w/w) glycerol, 30.20% (w/w) PEG400, 32.30% (w/w) Tween80, and 13.40% (w/w) Labrafil M1944CS, wherein gemcitabine hydrochloride is first added to water, NaOH, glycerol, and PEG400, then stirred until completely dissolved to form solution a, Tween80 is then mixed uniformly with Labrafil M1944CS to form solution B, and then mixed by pouring solution a into solution B to form the oral self-microemulsifying pharmaceutical composition;

(vii) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 2.00% (w/w) gemcitabine hydrochloride, 14.40% (w/w) water, 5.60% (w/w) 4.0N NaOH, 2.10% (w/w) glycerol, 30.20% (w/w) PEG400, 32.30% (w/w) Tween80, and 13.40% (w/w) Labrafil M1944CS, wherein gemcitabine hydrochloride is first added to water, NaOH, glycerol, and PEG400, then stirred until completely dissolved to form solution a, Tween80 is then mixed uniformly with Labrafil M1944CS to form solution B, and then mixed by pouring solution a into solution B to form the oral self-microemulsifying pharmaceutical composition; and

(viii) gexitabine oral self-microemulsifying pharmaceutical composition, which comprises: 2.00% (w/w) gemcitabine hydrochloride, 14.30% (w/w) water, 5.70% (w/w) 4.0N NaOH, 2.10% (w/w) 1, 2-propanediol, 30.20% (w/w) PEG400, 32.30% (w/w) Tween80, and 13.40% (w/w) Labrafil M1944CS, wherein gemcitabine hydrochloride is first added to water, NaOH, 1, 2-propanediol, and PEG400, then stirred until completely dissolved to form solution A, Tween80 is then uniformly mixed with Labrafil M1944CS to form solution B, and the oral self-microemulsifying pharmaceutical composition is then formed by pouring solution A into solution B and stirring and mixing.

10. A method of preparing the oral self-microemulsifying pharmaceutical composition of claim 1, which comprises mixing the hydrophilic drug or its pharmaceutically acceptable salt with the one or more solvents and the one or more hydrophilic carriers, and then mixing with the surfactant system to form the oral self-microemulsifying pharmaceutical composition.