EA045346B1 - PHARMACEUTICAL COMPOSITION CONTAINING METAARSENITE AND METHOD FOR ITS MANUFACTURE - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to pharmaceutical compositions containing sodium or potassium salt of metaarsenite, and methods for preparing pharmaceutical compositions. The present invention also relates to a method of treatment using pharmaceutical compositions.

State of the art

Cancer is an important health problem in the world. Despite advances in cancer detection and treatment, there is currently no vaccine or other universally successful preventative or therapeutic agent. Currently, treatment of the disease is based on a combination of early diagnosis and aggressive therapy, which may include one or more different types of therapies such as surgery, radiation therapy, chemotherapy and hormonal therapy. Although many patients benefit from these therapies, there is still a high mortality rate for many cancers. The development of improved anticancer agents will contribute to the prevention and treatment of cancer.

Unfortunately, cancer is the leading cause of death, second only to cardiovascular disease, in both men and women. Numerous methods have been developed to combat cancer and are the subject of ongoing research aimed at understanding the nature and cause of the disease and providing ways to control or cure it.

Although thousands of potential anticancer agents have been evaluated, the treatment of human cancer remains fraught with challenges that often present a range of suboptimal treatment options. In particular, chemotherapeutic agents that exhibit little or no toxicity, are inexpensive to obtain or manufacture, are well tolerated by the patient, and are easy to administer would be a desirable addition to the therapeutic modalities currently available to the oncologist. Also desirable are agents that will selectively sensitize malignant tissue, allowing lower doses of radiation or therapy to be used to achieve the same therapeutic effect with less damage to healthy tissue. Likewise, agents that prevent the occurrence or recurrence of cancer are also desirable.

Currently, many chemotherapy drugs have been developed for intravenous administration. Oral treatment with anticancer agents, however, is of interest due to the advantages of ease of administration, improved patient compliance, and reduced costs and improved quality of life for patients. For example, patients will be able to receive oral treatment on an outpatient basis. Thus, oral drugs for cancer treatment have a future and will play a more important role than in the past.

Arsenic compounds have been used as pharmaceuticals to treat a huge number of diseases, including cancer. Inorganic arsenic compounds are highly toxic. With the rapid development of medicine in the 20th century, the use of medicinal arsenic declined rapidly. Interest in arsenic compounds was renewed when it was demonstrated that daily intravenous administration of arsenic trioxide (As ₂ O ₃ ) alone produced complete responses in the vast majority of patients with newly diagnosed and relapsed acute promyelocytic leukemia. The disadvantage of arsenic trioxide is that it is administered intravenously daily through a 14-hour infusion over 6 weeks.

When arsenic trioxide is taken orally, it binds with chloride ions in the stomach and produces arsenic chloride ( _AsCl3 ). Arsenic chloride is toxic and has serious side effects. Due to the inherent toxicity of arsenic compounds when taken orally, interest in arsenic compounds for therapy remains low. However, oral formulations are noted to be easy to administer to patients and improve patient compliance.

Thus, there is a need for improved pharmaceutical compositions containing arsenic compounds suitable for oral administration for use in the treatment of diseases and conditions such as cancer and cancer pain.

The essence of the invention

The present inventor has developed an enteric-coated solid pharmaceutical composition containing sodium metaarsenite (O=As-O^-Na⁺) or potassium metaarsenite (O=As-O K⁺), which is suitable for oral administration and which passes through the stomach and begins to dissolve in the small intestine (where the acidity is in the pH range of 6.5-7.5).

In a first aspect, the present invention provides a pharmaceutical composition suitable for oral administration, comprising:

(a) a solid core comprising sodium metaarsenite or potassium metaarsenite and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients is selected to minimize oxidation of metaarsenite to metaarsenate; and (b) an enteric coating containing an enteric polymer; wherein the weight percentage of the enteric coating ranges from about 6% w/w. up to about 20%

- 1 045346 wt./wt. based on the total weight of the pharmaceutical composition, and the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

For example, in the above aspect, one or more pharmaceutically acceptable excipients may be selected from an excipient or diluent, a disintegrant, a glidant, a lubricant, and a binder. In some embodiments, the solid core may contain two or more of these excipients, three or more of these excipients, four or more of these excipients, or all of these excipients. Thus, in some embodiments, the solid core contains a filler or diluent, a disintegrant, a glidant, a lubricant, and a binder.

In a second aspect, the present invention provides a pharmaceutical composition suitable for oral administration, comprising:

(a) a solid core containing sodium metaarsenite or potassium metaarsenite and the following pharmaceutically acceptable excipients:

(i) a filler or diluent in the range of about 5 to 95% w/w, (ii) a disintegrant in the range of about 10 to 90% w/w, (iii) a glidant in the range of about 0.1 up to 5% w/w, (iv) lubricant in the range of about 0.1 to 5% w/w. and (v) optionally a binder in the range of from 0 to about 30% w/w; and (b) an enteric coating containing an enteric polymer;

wherein the pharmaceutically acceptable excipients are selected to minimize the oxidation of metaarsenite to metaarsenate, wherein the weight percentage of the enteric coating is from about 6% w/w. up to about 20% w/w based on the total weight of the pharmaceutical composition, and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

Those skilled in the art will appreciate that some excipients have multiple functions. If an excipient included in the pharmaceutical composition of the present invention has multiple functions, the pharmaceutical composition is considered to include excipients with these functions, for example, if the excipient acts as a binder and disintegrant, the pharmaceutical composition is understood to contain a binder and baking powder.

Preferably, the pharmaceutically acceptable excipients in the solid core have a low moisture level or low water activity to minimize the possibility of oxidation of metaarsenite to metaarsenate. Thus, it is preferable that the pharmaceutical composition of the present invention does not contain excipients with high moisture levels or high water activity.

The pharmaceutical composition may be presented in the form of an enteric-coated tablet or an enteric-coated capsule. In some embodiments, the pharmaceutical composition is an enteric-coated tablet. In some embodiments, the pharmaceutical composition is an enteric-coated capsule.

In a third aspect, the present invention provides a method for preparing a pharmaceutical composition according to the first aspect, the method comprising the following steps:

(a) mixing an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite with one or more pharmaceutically acceptable excipients to form a powder mixture, wherein the one or more pharmaceutically acceptable excipients is selected to minimize oxidation metaarsenite to metaarsenate;

(b) compressing the powder mixture obtained in step (a) to form a solid core; and (c) applying an enteric coating containing an enteric polymer to the solid core;

wherein the weight percentage of the enteric coating ranges from about 6% w/w. up to about 20% w/w based on the total weight of the pharmaceutical composition, and the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

In a fourth aspect, the present invention provides a method for making a pharmaceutical composition according to the second aspect, comprising the following steps:

(a) mixing an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite with the following pharmaceutically acceptable excipients to form a powder mixture:

(i) a filler or diluent in the range of from about 5 to 95% w/w,

- 2 045346 (ii) a disintegrant in the range of about 10 to 90% w/w, (iii) a glidant in the range of about 0.1 to 5% w/w, (iv) a lubricant in the range of about 0.1 to 5% w/w and (v) optionally a binder in the range of from 0 to about 30% w/w;

(b) compressing the powder mixture obtained in step (a) to form a solid core; and (c) applying an enteric coating containing an enteric polymer to the solid core;

wherein the pharmaceutically acceptable excipients are selected to minimize the oxidation of metaarsenite to metaarsenate, wherein the weight percentage of the enteric coating is from about 6% w/w. up to about 20% w/w based on the total weight of the pharmaceutical composition, and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

In a fifth aspect, the present invention provides a pharmaceutical composition according to the first or second aspect for use in treating a disease or condition, wherein the disease or condition is selected from solid malignancy, metastatic bone disease, metastatic neoplastic disease, primary or metastatic lung tumor, urogenital cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disorders, immunological disorders, diabetic retinopathy, diabetic vasculopathy, diabetic neuralgia, symptoms associated with insulitis, and ulcerative colitis.

In a sixth aspect, the present invention provides a method of treating a disease or condition in a subject, comprising orally administering to the subject a pharmaceutical composition of the first or second aspect, wherein the disease or condition is selected from solid malignancy, metastatic bone disease, metastatic neoplastic disease, primary or metastatic lung tumor , urogenital cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disorders, immunological disorders, diabetic retinopathy, diabetic vasculopathy, diabetic neuralgia, symptoms associated with insulitis, and ulcerative colitis.

In a seventh aspect, the present invention provides the use of a pharmaceutical composition according to the first or second aspect for the manufacture of an oral medicament for the treatment of a disease or condition, wherein the disease or condition is selected from solid malignancy, metastatic bone disease, metastatic neoplastic disease, primary or metastatic lung tumor, urogenital cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disorders, immunological disorders, diabetic retinopathy, diabetic vasculopathy, diabetic neuralgia, symptoms associated with insulitis, and ulcerative colitis.

Detailed Description of Embodiments of the Invention

Preferred embodiments of the present invention are described below by way of example only.

1. Definitions

Unless otherwise specified herein, the following terms should be understood to have the following general meanings. The terms mentioned below have the general meanings that follow when the term is used alone and when the term is used in combination with other terms, unless otherwise noted.

The term composition covers compositions and formulations containing an active pharmaceutical ingredient (API) with excipients or carriers, as well as compositions and formulations with encapsulating materials as a carrier to form a capsule in which the active pharmaceutical ingredient (with or without other carriers) is surrounded carrier for encapsulation. In pharmaceutical compositions, the excipient or carrier is pharmaceutically acceptable, meaning that it is not biologically or otherwise undesirable, i.e. the substance may be included in a pharmaceutical composition administered to a patient without causing any undesirable biological effects or harmful interaction with any of the other components of the composition in which it is contained.

By pharmaceutically acceptable, for example, as in the description of a pharmaceutically acceptable salt or a pharmaceutically acceptable excipient or carrier herein, is meant a substance that is not biologically or otherwise undesirable, i.e. the substance may be included in a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a harmful manner with any of the other components of the composition in which it is contained.

The term effective amount or therapeutically effective amount refers to an amount of active pharmaceutical ingredient that is sufficient to produce the same

- 3 045346 desired therapeutic response without undesirable side effects (such as toxicity, irritation or allergic response), commensurate with an acceptable benefit/risk ratio when used in the method of the present invention. This amount, for example, may be effective in delaying growth, delaying metastasis, inhibiting angiogenesis and/or telomeres, and/or causing tumor shrinkage. The specific effective amount or therapeutically effective amount will vary depending on factors such as the specific condition being treated, age, body weight, general health, physical condition, sex and diet of the subject, duration of treatment, nature of concomitant therapy (if any) and the severity of the specific condition.

As used herein, the term about means a slight deviation from the specified value, preferably in the range of 10 percent from the specified value. However, the term about may imply a higher tolerance depending, for example, on the experimental method used. Said deviations (variations) of the specified value are understandable to a person skilled in the art and are within the context of the present invention. In addition, to provide a more concise description, some of the quantitative expressions provided herein are not defined by the term about. It is understood that, whether the term about is expressly used or not, each quantity stated herein is intended to refer to an actual given quantity and is also intended to refer to an approximate value of such given quantity that would be reasonably included on the basis of standard knowledge in the art, including equivalents and approximations due to experimental and/or measurement conditions for such a given quantity.

Unless otherwise indicated, all amounts are expressed herein as percentages by weight (% w/w).

Of course, any substance used to prepare the pharmaceutical composition of the present invention must be pharmaceutically pure and substantially non-toxic in the amounts used.

2. Chemistry of metaarsenite salts

Sodium metaarsenite and potassium metaarsenite can be synthesized from arsenic trioxide (As ₂ O ₃ ). For example, sodium metaarsenite can be synthesized by reacting arsenic trioxide (As ₂ O ₃ ) with an aqueous solution of sodium hydroxide to form trivalent sodium metaarsenite (top left in Scheme 1 below). The solution is cooled, sodium metaarsenite is filtered and the water is evaporated. The resulting sodium metaarsenite is then washed with methanol to remove water, filtered under vacuum and then dried. Potassium metaarsenite can be prepared in a similar manner to sodium metaarsenite by using an aqueous solution of potassium hydroxide instead of an aqueous solution of sodium hydroxide.

However, the main problem with metaarsenite salt (O=As-O salt) is its chemical composition and its ability to convert into a number of different forms in solution, such as when an oral dosage form containing sodium metaarsenite (O=As-O ^- Na ⁺ ) or metaarsenite potassium (O=As-O ^- K ⁺ ), dissolves in the stomach. For example, sodium metaarsenite (O=As-O ^- Na ⁺ ) dissolves easily in a strong acid, in a strong base and in neutral conditions. The forms present depend on the pH of the solution and the tendency of sodium metaarsenite to oxidize (Scheme 1 below). Potassium metaarsenite behaves similarly to sodium metaarsenite. In general, neutral to alkaline conditions favor the formation (or retention) of As(III) (arsenite), while acidic conditions (especially in the presence of chloride ions, such as in the stomach) favor the formation of As(V) (arsenate) .

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Scheme 1

Additionally, metaarsenite (O=As-O) can be oxidized to metaarsenate during storage when chloride ions, metal ions, or moisture are present (e.g., in the dissolution medium or within excipients; excipients can catalyze the oxidation, e.g. substances with metal ions, in particular iron), or atmospheric oxygen. Oxidation of metaarsenite can occur quite quickly at low pH values. Sodium metaarsenite (O=As-O'Na ⁺ ) and potassium metaarsenite (O-As-OK) are both hygroscopic.

In solution, the main substance that decomposes sodium metaarsenite is pentavalent sodium metaarsenate (AsO ₄ ³ 'or As(V)), formed as a result of the oxidation reaction. It is assumed that this may occur as shown in the table below. 1, however, theoretically, oxidation (change in valence) can occur without oxygen uptake (for example, by interaction with an excipient or by reaction with metal ions present in sodium metaarsenite or compositions).

Table 1

Restored form Oxidized form

As ³⁺ As ⁵⁺ + 2e' change in valence of As (Formula!)

AsOz' + O ₂ AsO?' oxygen absorption (Formula 2)

Another difficulty arising from the dissolution of sodium metaarsenite (O-As-OAa) or potassium metaarsenite (O=As-O'K ⁺ ) in the stomach is the formation of arsenic chloride (AsCl ₃ ) from chloride ions in the stomach . Oxidation of metaarsenite can occur faster when chloride is present. Arsenic(III) chloride is toxic to humans and causes serious side effects.

The present inventor has developed an enteric-coated solid pharmaceutical composition containing sodium metaarsenite or potassium metaarsenite, which is suitable for oral administration, and which passes through the stomach and begins to dissolve in the small intestine (where the acidity is in the pH range of 6.5-7.5) . The risk of oxidation of the metaarsenite form to the metaarsenate form (in the stomach or during storage) and the risk of formation of toxic arsenic(III) chloride from chloride ions in the stomach are minimized by the use of suitable excipients and carriers, and a suitable enteric coating of suitable thickness. Dissolution of the enteric-coated solid pharmaceutical composition in the small intestine may occur rapidly or over a longer period of time (e.g., 0.5, 0.75, 1, 2, 3, 4, 5, or 6 hours, preferably within 2 hours) .

Preferred embodiments of the pharmaceutical composition of the present invention are described below. The pharmaceutical composition of the present invention can be manufactured using effective methods described below.

3. Pharmaceutical composition of the present invention

In a first aspect, the present invention provides a pharmaceutical composition suitable for oral administration, comprising:

(a) a solid core comprising sodium metaarsenite or potassium metaarsenite and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients is selected to minimize oxidation of metaarsenite to metaarsenate; and (b) an enteric coating containing an enteric polymer;

-5045346 wherein the weight percentage of the enteric coating ranges from about 6% w/w. up to about 20% w/w based on the total weight of the pharmaceutical composition, and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

For example, in the above aspect, one or more pharmaceutically acceptable excipients may be selected from an excipient or diluent, a disintegrant, a glidant, a lubricant, and a binder. In some embodiments, the solid core may contain two or more of these excipients, three or more of these excipients, four or more of these excipients, or all of these excipients. Thus, in some embodiments, the solid core contains a filler or diluent, a disintegrant, a glidant, a lubricant, and a binder.

In a second aspect, the present invention provides a pharmaceutical composition suitable for oral administration, comprising:

(a) a solid core containing sodium metaarsenite or potassium metaarsenite and the following pharmaceutically acceptable excipients:

(i) a filler or diluent in the range of about 5 to 95% w/w, (ii) a disintegrant in the range of about 10 to 90% w/w, (iii) a glidant in the range of about 0.1 up to 5% w/w, (iv) lubricant in the range of about 0.1 to 5% w/w. and (v) optionally a binder in the range of from 0 to about 30% w/w; and (b) an enteric coating containing an enteric polymer; wherein the pharmaceutically acceptable excipients are selected to minimize the oxidation of metaarsenite to metaarsenate, wherein the weight percentage of the enteric coating is from about 6% w/w. up to about 20% w/w based on the total weight of the pharmaceutical composition, and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

The pharmaceutical composition may be in the form of an enteric-coated tablet or an enteric-coated capsule. In some embodiments, the pharmaceutical composition is an enteric-coated tablet. In some embodiments, the pharmaceutical composition is an enteric-coated capsule.

3.1 Active pharmaceutical ingredient (API) (sodium or potassium metaarsenite)

In the pharmaceutical composition of the present invention, the active pharmaceutical ingredient (API) is sodium metaarsenite or potassium metaarsenite.

Sodium metaarsenite and potassium metaarsenite can be produced industrially in high purity (>98% As(III) and minimal levels of As(V)). Sodium metaarsenite and potassium metaarsenite are hygroscopic.

Being inorganic compounds, sodium metaarsenite and potassium metaarsenite each have a higher (true) particle density (e.g., approximately 2.1-2.3 g/ ^cm3 for sodium metaarsenite and about 8.76 g/ ^cm3 for potassium metaarsenite) compared to the excipients of a typical tablet (the excipients of a typical tablet are usually organic substances whose density is approximately 1.2-1.6 g/cm ³ ).

The likelihood of API segregation in compositions is high when there are differences in API particle size and excipient particle size. One skilled in the art will appreciate that the use of the preferred particle size of the API advantageously results in improved mixing of powders and uniformity of the mixture, minimizes or eliminates segregation in powders during compression, and provides satisfactory uniformity of composition in the compositions.

In some embodiments, the API particle size is about 50-150 microns. In some embodiments, the API particle size is about 70-120 microns. In some embodiments, the API particle size is about 90-100 microns.

In some embodiments, the API is sodium metaarsenite.

In some embodiments, the API is potassium metaarsenite.

In some embodiments, the amount of API in the solid core of the pharmaceutical composition of the present invention is about 0.1-5.0% w/w. solid core, preferably about 0.5-3.0% wt./wt. solid core, more preferably about 1.0-2.5% wt./wt. hard core, even more preferably about 1.5-2.0% wt./wt. solid core and most preferably about 1.6-1.8% wt./wt. hard core, for example, about 1.65% w/w, about 1.66% w/w, about 1.67% w/w, about 1.68% w/w, about 1.69% w/w, about 1.70% w/w, about 1.71% w/w, about 1.72% w/w, about 1.73% w/w /wt., about 1.74% wt./wt. or about 1.75% w/w. hard core.

- 6 045346

In some embodiments, the particle size of the API and the particle size of the pharmaceutically acceptable excipients are comparable. Preferably using APIs and excipients with comparable particle sizes can result in improved powder mixing and blend uniformity, can minimize or eliminate segregation in powders during compression, and can provide satisfactory uniformity of composition in the compositions.

In some embodiments, the API is micronized. One skilled in the art will appreciate that reducing API particle size by micronization can improve mixture uniformity and formulation uniformity in dosage forms (such as tablets) when API is present at low concentrations.

In some embodiments, the API is not micronized. One skilled in the art will appreciate that micronization of hygroscopic APIs (such as sodium metaarsenite and potassium metaarsenite) may result in an increased risk of degradation due to greater surface area and reactivity.

3.2 Pharmaceutically acceptable excipients

In one aspect, in addition to sodium metaarsenite or potassium metaarsenite, the solid core of the pharmaceutical composition of the present invention contains one or more pharmaceutically acceptable excipients that are selected to minimize the oxidation of metaarsenite to metaarsenate.

In some embodiments, the pharmaceutically acceptable excipients are selected to be less than about 10% w/w, preferably less than about 5% w/w, more preferably less than about 2% w/w, even more preferably less than about 1% w/w. and most preferably less than about 0.5% w/w. sodium metaarsenite or potassium metaarsenite is oxidized to sodium metaarsenate or potassium metaarsenate after storage at room temperature for at least about 1 month, preferably at least about 2 months, more preferably at least about 3 months, even more preferably at least about 4 months and most preferably at least about 6 months.

In another aspect, in addition to sodium metaarsenite or potassium metaarsenite, the solid core of the pharmaceutical composition of the present invention contains the following pharmaceutically acceptable excipients:

(i) a filler or diluent, (ii) a disintegrant, (iii) a glidant, (iv) a lubricant, and (v) optionally a binder.

Those skilled in the art will appreciate that some excipients perform multiple functions. If an excipient included in a pharmaceutical composition of the present invention performs multiple functions, the pharmaceutical composition is said to include excipients with those functions, for example, if an excipient acts as a binder and disintegrant, the pharmaceutical composition is understood to contain a binder and baking powder.

Typically, one or more pharmaceutically acceptable excipients in the solid core are compatible with sodium or potassium metaarsenite. It is preferable that the pharmaceutically acceptable excipients in the solid core have low moisture levels or low activity in water to minimize the possibility of oxidation of metaarsenite to metaarsenate. Thus, it is preferable that the pharmaceutical composition of the present invention does not contain excipients with high moisture levels or high water activity (such excipients can catalyze oxidation, for example, excipients with metal ions, in particular iron). However, those skilled in the art will appreciate that there is a limit to the practical applicability of this requirement for the pharmaceutical composition of the present invention, since some available moisture is required for satisfactory compression.

In some embodiments, the particle size of the API and the particle size of the pharmaceutically acceptable excipients are comparable. Preferably using APIs and excipients with comparable particle sizes can result in improved powder mixing and mixture uniformity, can minimize or eliminate segregation in powders during compression, and can provide satisfactory uniformity of solid core composition.

In some embodiments, where possible, higher density versions of the base excipients are selected to match the density of sodium or potassium metaarsenite (sodium metaarsenite has an estimated true density of approximately 2.1-2.3 g/cm ³ and potassium metaarsenite has estimated true density of approximately 8.76 g/cm ³ ); Typical tablet excipients, which are organic substances, have a density of approximately 1.2-1.6 g/cm ³ .

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The filler or diluent may, for example, be selected from anhydrous dibasic calcium phosphate, partially pregelatinized starch, silicated microcrystalline cellulose, microcrystalline cellulose, calcium sulfate dihydrate, lactose, hydrogen calcium phosphate, calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, or a mixture thereof. In some embodiments, the filler or diluent is anhydrous dibasic calcium phosphate, partially pregelatinized starch, or a mixture thereof. In some embodiments, the filler or diluent is anhydrous dibasic calcium phosphate. In some embodiments, the filler or diluent is partially pregelatinized starch. In some embodiments, the diluent may be a compressible diluent, such as silicated microcrystalline cellulose, microcrystalline cellulose, or partially pregelatinized starch.

The filler or diluent may be present in the solid core of the pharmaceutical composition in an amount from about 5 to 95% w/w. hard core. In some embodiments, the filler or diluent is present in the solid core of the pharmaceutical composition in an amount of from about 10 to 90% w/w. hard core, for example about 10% wt./wt. hard core, about 15% w/w. hard core, about 20% w/w. hard core, about 25% wt./wt. hard core, about 30% w/w. hard core, about 35% wt./wt. hard core, about 40% w/w. hard core, about 45% w/w. solid core, about 50% wt./wt. solid core, about 55% wt./wt. solid core, about 60% wt./wt. solid core, about 65% w/w. solid core, about 70% wt./wt. solid core, about 75% wt./wt. solid core, about 80% wt./wt. solid core, about 85% wt./wt. solid core or about 90% wt./wt. hard core.

The disintegrant may, for example, be selected from L-hydroxypropylcellulose, partially pregelatinized starch, crospovidone, potato starch, corn starch, sodium starch glycolate and alginic acid. Sodium starch glycolate and crospovidone are super leavening agents. In some embodiments, the disintegrant is Lhydroxypropylcellulose, partially pregelatinized starch, sodium starch glycolate, or a mixture of two or more of these. In some embodiments, the disintegrant is Lhydroxypropylcellulose. In some embodiments, the leavening agent is partially pregelatinized starch. In some embodiments, the leavening agent is sodium starch glycolate.

The disintegrant may be present in the solid core of the pharmaceutical composition in an amount from about 10 to 90% w/w. solid core, for example from about 10 to 50% wt./wt. hard core. In some embodiments, the disintegrant is present in the solid core of the pharmaceutical composition in an amount from about 15 to 85% w/w. hard core, for example about 15% wt./wt. hard core, about 20% w/w. hard core, about 25% wt./wt. hard core, about 30% w/w. hard core, about 35% wt./wt. hard core, about 40% w/w. hard core, about 45% w/w. solid core, about 50% wt./wt. solid core, about 55% wt./wt. solid core, about 60% wt./wt. solid core, about 65% w/w. solid core, about 70% wt./wt. solid core, about 75% wt./wt. solid core, about 80% wt./wt. solid core or about 85% wt./wt. hard core.

The glidant may, for example, be selected from colloidal silicon dioxide and talc. In some embodiments, the glidant is colloidal silica. In some embodiments, the glidant is talc.

The glidant may be present in the solid core of the pharmaceutical composition in an amount of from about 0.1 to 5% w/w. hard core. In some embodiments, the glidant is present in the solid core of the pharmaceutical composition in an amount of from about 0.3 to 4% w/w. hard core, for example about 0.3% wt./wt. hard core, about 0.4% w/w. hard core, about 0.5% w/w. hard core, about 0.6% w/w. hard core, about 0.7% w/w. hard core, about 0.8% w/w. hard core, about 0.9% w/w. hard core, about 1.0% w/w. hard core, about 1.1% w/w. hard core, about 1.2% w/w. hard core, about 1.3% w/w. hard core, about 1.4% w/w. hard core, about 1.5% w/w. hard core, about 1.6% w/w. hard core, about 1.7% w/w. hard core, about 1.8% w/w. hard core, about 1.9% w/w. hard core, about 2.0% w/w. hard core, about 2.1% w/w. hard core, about 2.2% w/w. hard core, about 2.3% w/w. hard core, about 2.4% w/w. hard core, about 2.5% w/w. hard core, about 2.6% w/w. hard core, about 2.7% w/w. hard core, about 2.8% w/w. hard core, about 2.9% w/w. hard core, about 3.0% w/w. hard core, about 3.1% w/w. hard core, about 3.2% w/w. hard

- 8 045346 cores, about 3.3% w/w. hard core, about 3.4% w/w. hard core, approx.

3.5% w/w hard core, about 3.6% w/w. hard core, about 3.7% w/w.

hard core, about 3.8% w/w. hard core, about 3.9% w/w. hard core or about 4.0% w/w. hard core.

The lubricant may, for example, be selected from sodium stearyl fumarate, magnesium stearate, stearic acid, talc and silicon dioxide. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is talc. In some embodiments, the lubricant is silica.

The lubricant may be present in the solid core of the pharmaceutical composition in an amount of from about 0.1 to 5% w/w. hard core. In some embodiments, the lubricant is present in the solid core of the pharmaceutical composition in an amount of from about 0.3 to 4% w/w. hard core, for example about 0.3% wt./wt. hard core, about 0.4% w/w. hard core, about 0.5% w/w. hard core, about 0.6% w/w. hard core, about 0.7% w/w. hard core, about 0.8% w/w. hard core, about 0.9% w/w. hard core, about 1.0% w/w. hard core, about 1.1% w/w. hard core, about 1.2% w/w. hard core, about 1.3% w/w. hard core, about 1.4% w/w. hard core, about 1.5% w/w. hard core, about 1.6% w/w. hard core, about 1.7% w/w. hard core, about 1.8% w/w. hard core, about 1.9% w/w. hard core, about 2.0% w/w. hard core, about 2.1% w/w. hard core, about 2.2% w/w. hard core, about 2.3% w/w. hard core, about 2.4% w/w. hard core, about 2.5% w/w. hard core, about 2.6% w/w. hard core, about 2.7% w/w. hard core, about 2.8% w/w. hard core, about 2.9% w/w. hard core, about 3.0% w/w. hard core, about 3.1% w/w. hard core, about 3.2% w/w. hard core, about 3.3% w/w. hard core, about 3.4% w/w. hard core, about 3.5% w/w. hard core, about 3.6% w/w. hard core, about 3.7% w/w. hard core, about 3.8% w/w. hard core, about 3.9% w/w. hard core or about 4.0% w/w. hard core.

The binder, if present, may, for example, be selected from silicated microcrystalline cellulose, microcrystalline cellulose, partially pregelatinized starch, L-hydroxypropylcellulose (low-substituted hydroxypropylcellulose), hydroxypropylcellulose, copovidone (polyvinylpyrrolidone), pregelatinized corn starch, hydroxypropyl methylcellulose, starch, arabic gums , corn starch and gelatin. In some embodiments, the binder is Lhydroxypropylcellulose (low-substituted hydroxypropylcellulose). In some embodiments, the binder is a mixture of L-hydroxypropylcellulose (low-substituted hydroxypropylcellulose) and hydroxypropylcellulose. In some embodiments, the binder is partially pregelatinized starch.

The binder may be present in the solid core of the pharmaceutical composition in an amount of from about 0 to 30% w/w. hard core. In some embodiments, the binder is present in the solid core of the pharmaceutical composition in an amount of from about 1 to 30% w/w. hard core, for example from about 5 to 25% wt./wt. hard core. For example, the binder may be present in the solid core of the pharmaceutical composition in an amount of from about 5% wt./wt. hard core, about 10% w/w. hard core, about 15% w/w. hard core, about 20% w/w. hard core, about 25% wt./wt. hard core, about 30% w/w. hard core.

The pharmaceutical composition of the present invention may optionally contain an antioxidant in the solid core. Antioxidants act as reducing agents by: (a) reducing redox potential, (b) scavenging oxygen, or (c) stopping free radical reactions (acting as free radical inhibitors). Mechanisms (a) and (b) are most important for the decomposition of sodium or potassium metaarsenite to sodium or potassium metaarsenate. Predominantly, the effect of the antioxidant is aimed at reducing or preventing the oxidation of As(III) to As(V) in the composition.

Examples of antioxidants that can be used in the solid core include sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium sulfate, sodium thiosulfate, cysteine hydrochloride, ascorbic acid, propyl gallate, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).

The antioxidant may be present in the solid core in an amount of from about 0.01 to 0.2% w/w, for example 0.01% w/w, 0.02% w/w, 0.03% w/w ./wt., 0.04% wt./wt., 0.05% wt./wt.,

- 9 045346

0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.11% w/w,

0.12% w/w, 0.13% w/w, 0.14% w/w, 0.15% w/w, 0.16% w/w, 0.17% w/w,

0.18% w/w, 0.19% w/w or 0.20% w/w hard core.

One skilled in the art will appreciate that the amounts of API (sodium metaarsenite or potassium metaarsenite), excipients and other ingredients in the solid core are adjusted to be 100% of the solid core.

Advantageously, the solid core of the pharmaceutical composition of the present invention has good mixture uniformity and uniformity of composition due to the use of suitable excipients as described above.

In some embodiments, the solid core of the pharmaceutical composition of the present invention does not contain any one or more of the following: silicated microcrystalline cellulose, microcrystalline cellulose, calcium sulfate dihydrate, copovidone (polyvinylpyrrolidone), crospovidone, stearic acid, talc, and sodium metabisulfite.

3.3 Enteric coating

The pharmaceutical composition of the present invention includes an enteric coating containing an enteric polymer. The enteric coating can be applied using suitable coating techniques known in the art. The enteric coating material can be dispersed or dissolved in either water or suitable organic solvents.

As enteric coating polymers, one or more of the following may be used, alone or in combination, for example: solutions or dispersions of copolymers of acrylic acids and their esters or methacrylic acids or their esters, polysorbates, cellulose acetate phthalate polymers, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating polymer(s).

In some embodiments, the enteric coating is a methacrylate-based coating, for example, comprising a copolymer of methacrylic acid and ethyl acrylate. Several useful products are commercially available.

Resin products for enteric coating are available from Rohm GmbH & Co., Darmstadt, Germany under the EUDRAGIT® brand name, including L100, L100-55 and S100. Examples of useful EUDRAGIT® products include Eudragit L100-55, Eudragit S100 and EUDRAGIT L30D-55. Eudragit L100-55 is a poly(methacrylic acid-co-ethyl acrylate) (1:1). EUDRAGIT S100 is a copolymer of methacrylic acid and methyl methacrylate (1:2). EUDRAGIT L30D-55 is an aqueous dispersion of a pH-sensitive polymer, soluble at pH 5.5 or higher, for targeted delivery to the duodenum. EUDRAGIT L30D-55 methacrylic acid copolymer is a 1:1 copolymer of methacrylic acid and ethyl acrylate and has the formula (C ₅ H2O2'C4H6O2)x.

Colorcon's Acryl-EZE® is a water-dispersible, aqueous acrylic enteric coating system for enteric film coating of solid dosage forms such as tablets, granules and pellets. Examples of useful Acryl-EZE® products include Acryl-EZE II White (493Z180022) and Acryl-EZE Green (93011863).

The enteric coating may further contain pharmaceutically acceptable plasticizers to provide desired mechanical properties such as flexibility and hardness of the enteric coating. Such plasticizers include, for example, but are not limited to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers. Anti-blocking agents such as, for example, magnesium stearate, titanium dioxide, talc and other additives may also be included in the enteric coating.

In some embodiments, the enteric coating provides a weight gain of from about 7% to 17% w/w. solid core, for example, a weight gain of from about 8% to 14% w/w. hard core. In some embodiments, the enteric coating provides a weight gain of about 8% w/w, a weight gain of about 8.5% w/w, a weight gain of about 9% w/w, a weight gain , being about 9.5% w/w, a weight gain of about 10% w/w, a weight gain of about 10.5% w/w, a weight gain of about 11% w/w. /wt., weight gain of about 11.5% wt./wt., weight gain of about 12% wt./wt., weight gain of about 12.5% wt./wt., weight gain, of about 13% w/w, a weight gain of about 13.5% w/w, or a weight gain of about 14% w/w. In some embodiments, the enteric coating provides a weight gain of about 12% w/w. hard core.

In some embodiments, the solid core may be coated with an intermediate

- 10 045346 layer before applying an enteric coating using polymers known in the art to be suitable for the intermediate layer.

3.4 Forms of the pharmaceutical composition of the present invention

The pharmaceutical composition of the present invention is an enteric-coated solid and is suitable for oral administration, such as enteric-coated tablets or enteric-coated capsules.

In some embodiments, the pharmaceutical composition of the present invention is an enteric-coated tablet that has a hard core having a diameter of about 5 to 8 mm. The diameter is the diameter of the widest dimension of the solid core. In some embodiments, the diameter of the solid core is from about 5.5 m to 7.5 mm. In some embodiments, the diameter of the solid core is from about 6.0 to 7 mm, such as about 6 mm, about 6.5 mm, or about 7 mm.

Preferably, the pharmaceutical composition of the present invention is an enteric-coated tablet which has a hard core with a diameter of 6.5 mm. More preferably, the pharmaceutical composition of the present invention is an enteric-coated tablet which has a hard core with a diameter of 6.5 mm and which contains sodium metaarsenite.

In some embodiments, the thickness of the enteric-coated tablet hard core may be from about 2 to 6 mm, such as from about 2 to 5 mm. The hard core thickness of an enteric coated tablet is the hard core depth, that is, the height of the hard core measured with the hard core lying on a flat surface. In some embodiments, the hard core thickness of the enteric-coated tablet is approximately 3-4.5 mm. In some embodiments, the thickness of the enteric-coated tablet hard core is about 3.1-4.2 mm, such as about 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm, about 3. 5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9 mm, about 4.0 mm, about 4.1 mm, or about 4.2 mm. Preferably, the thickness of the enteric-coated tablet hard core is about 3.4 mm, about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, or about 3.9 mm.

In some embodiments, the pharmaceutical composition of the present invention is an enteric-coated capsule that has a hard core having a length of from about 8.0 to 16 mm. In some embodiments, the length of the solid core is approximately 8.5-15 mm. In some embodiments, the hard core length is about 8.5-14.5 mm, such as about 8.5 mm, about 9.0 mm, about 9.5 mm, about 10.0 mm, about 10.5 mm, about 11.0mm, about 11.5mm, about 12.0mm, about 12.5mm, about 13.0mm, about 13.5mm, about 14 or about 14.5mm. Preferably, the pharmaceutical composition of the present invention is an enteric-coated capsule that has a hard core with a length of about 14.3 mm. More preferably, the pharmaceutical composition of the present invention is an enteric-coated capsule which has a hard core having a length of about 14.3 mm and which contains sodium metaarsenite.

In some embodiments, the hard core thickness of the enteric-coated capsule may be from about 3 to 8 mm, such as from about 4.0 to 7.0 mm. The thickness of the hard core of an enteric coated capsule is the depth of the hard core, that is, the height of the hard core measured when the hard core is on a flat surface. In some embodiments, the solid core thickness is about 4.5-6.5 mm, such as about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, about 5.0mm, about 5.1mm, about 5.2mm, about 5.3mm, about 5.4mm, about 5.5mm, about 5.6mm, about 5.7mm, about 5. 8mm, about 5.9mm, about 6.0mm, about 6.1mm, about 6.2mm, about 6.3mm, about 6.4mm or about 6.5mm. Preferably, the thickness of the hard core of the enteric-coated capsule is about 5.31 mm.

In some embodiments, the hardness of the solid core is from about 50 to about 200 N, such as from about 50 to about 150 N, or from about 70 to about 120 N. In some embodiments, the hardness of the hard core is from about 80 to about 115 N, for example, about 85 N, about 90 N, about 95 N, about 100 N, about 105 N, or about 110 N. In some embodiments, the hardness of the solid core is at least about 50 N, at least about 55 N, at least about 60 N, at least about 65 N, at least about 70 N, at least about 75 N, at least about 80 N, at least about 85 N, at least about 90 N, at least about 95 N, at least about 100 N, at least about 105 N, at least about 110 N, at least about 115 N, at least about 120 N, at least about 125 N, at least about 130 N, at least about 135 N, at least about 140 N, at least about 145 N, at least about 150 N, at least about 155 N, at least about 160 N, at least about 165 N , at least about 170 N, at least about

- 11 045346

175 N, at least about 180 N, at least about 185 N, at least about 190 N, at least about 195 N, or about 200 N. Preferably, the hardness of the solid core is at least about 85 N, more preferably at least about 90 N, even more preferably at least about 100 N, and most preferably at least about 110 N. Typically, the hardness of the solid core does not exceed about 210 N.

In some embodiments, the hard core friability is less than about 0.5%, preferably less than about 0.45%, more preferably less than about 0.4%, even more preferably less than about 0.35%, and most preferably less than about 0.3%. In some embodiments, the hard core fragility is less than about 0.25%. In some embodiments, the hard core fragility is less than about 0.2%. In some embodiments, the hard core fragility is less than about 0.15%. In some embodiments, the friability of the solid core is less than about 0.1%, such as about 0.08%.

In some embodiments, the solid core weight is from about 50 to 250 mg. In some embodiments, the solid core weight is from about 80 to 220 mg. In some embodiments, the solid core weight is from about 100 to 200 mg. In some embodiments, the solid core weight is from about 120 to 180 mg. In some embodiments, the solid core weight is from about 140 to 160 mg, such as about 140 mg, about 145 mg, about 150 mg, about 155 mg, or about 160 mg. Preferably the solid core weight is 150 mg.

In some embodiments, the pharmaceutical composition of the present invention contains a solid core selected from a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate, L-hydroxypropylcellulose, hydroxypropylcellulose, colloidal silicon dioxide and sodium stearyl fumarate;

a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate powder, partially pregelatinized starch, anhydrous dibasic calcium phosphate, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate;

a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate powder, anhydrous dibasic calcium phosphate, L-hydroxypropylcellulose, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate;

a hard core containing sodium metaarsenite, anhydrous dibasic calcium phosphate, partially pregelatinized starch, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate; and a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate, silicated microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate.

In some embodiments, the pharmaceutical composition of the present invention is an enteric-coated tablet containing 1.67% w/w. sodium metaarsenite solid core, and having a solid core diameter of about 6.5 mm, a solid core weight of 150 mg, and an enteric coating that adds about 12% w/w. hard core.

In some embodiments, the pharmaceutical composition of the present invention is an enteric-coated tablet containing 1.67% w/w. sodium metaarsenite hard core and having a hard core diameter of about 6.5 mm, a hard core weight of 150 mg, and an enteric coating having a coating thickness of about 0.2 mm.

In some embodiments, after administration of the pharmaceutical composition of the present invention, the pharmaceutical composition has the following dissolution properties: not less than 75% in 45 minutes, preferably not less than 75% in 30 minutes.

In some embodiments, dissolution of the pharmaceutical composition of the present invention and release of the API in the small intestine occurs rapidly or occurs over a long period of time (e.g., 0.5, 0.75, 1, 2, 3, 4, 5, or 6 hours, preferably within 2 hours).

In some embodiments, upon dissolution of the enteric coating, the solid core disintegrates in less than about 10 minutes, preferably in less than about 8 minutes, more preferably in less than about 6 minutes, even more preferably in less than about 5 minutes, and most preferably in less than approximately 4 min.

The pharmaceutical composition of the present invention is preferably presented in unit dosage form. The unit dosage form may be a packaged preparation, the package containing individual quantities of the pharmaceutical composition, for example, packaged tablets or capsules. In addition, the unit dosage form may be a tablet or capsule by itself, or it may be a corresponding number of any of them in packaged form. The packaged form may, for example, contain metal or plastic foil, such as blister packs such as Alu-Alu blisters, which are impermeable or less permeable to oxygen. Instructions for use may be included with the packaged form.

In some embodiments, the pharmaceutical composition of the present invention may be stored at ambient or room temperature for at least three months, preferably at least six months, more preferably at least one year, and most preferably for 18-24 months . In some embodiments, the pharmaceutical composition of the present invention can be stored in a refrigerator (eg, at a temperature of about 2-8°C).

3.5 Dosages

Suitable dosages of sodium or potassium meta-arsenite can be readily determined by one skilled in the art.

A suitable dosage level of sodium or potassium meta-arsenite administered to a subject will generally be about 0.01-0.8 mg/kg subject's body weight per day, for example about 0.05-0.7 mg/kg subject's body weight per day , about 0.1-0.6 mg/kg of subject's body weight per day, or about 0.2-0.5 mg/kg of subject's body weight per day, which can be administered once or multiple times per day.

For example, a suitable daily dosage level of sodium or potassium meta-arsenite administered to a patient (eg, a patient having cancer) may be about 2.0-30 mg/day, for example, about 2.5-20.0 mg/day or about 2.5-17.5 mg/day. Preferably, the dosage level of sodium or potassium metaarsenite administered is about 5.0-12.5 mg/day, more preferably about 10.0-12.5 mg/day, e.g., 5.0 mg/day, 5.5 mg/day , 6.0 mg/day, 6.5 mg/day, 7.0 mg/day, 7.5 mg/day, 8.0 mg/day, 8.5 mg/day, 9.0 mg/day, 9.5 mg/day, 10.0 mg/day, 10.5 mg/day, 11.0 mg/day, 11.5 mg/day, 12.0 mg/day, or 12.5 mg/day.

It will be understood that the specific dose level and dosing frequency for any particular subject may vary and will depend on a variety of factors, including age, body weight, general health, sex and diet of the subject, dosage regimen and timing, elimination rate, drug combinations, and severity specific condition.

The pharmaceutical composition of the present invention can be taken before (eg, 30 minutes before) a meal, during a meal, or after (eg, 30 minutes after) a meal. Preferably, the pharmaceutical composition of the present invention is taken immediately after meals.

An exemplary dosage regimen for a tablet of the present invention containing 2.5 mg sodium metaarsenite (SMA) is presented below:

taking 5.0 mg SMA: 1x tablet immediately after breakfast, 1x tablet immediately after dinner;

taking 7.5 mg SMA: 2 tablets immediately after breakfast, 1 tablet immediately after dinner;

taking 10.0 mg SMA: 2 tablets immediately after breakfast, 2 tablets immediately after dinner.

3.6 Application

The pharmaceutical composition of the present invention is suitable for clinical use in the treatment of various diseases and conditions.

The pharmaceutical composition according to the invention can, for example, be used to treat the following diseases and conditions:

solid malignant tumor such as colon tumor, stomach tumor, breast tumor, ovarian tumor, prostate tumor and kidney tumor (solid malignant tumors belonging to the group consisting of colon tumor, breast tumor, prostate tumor and tumor kidneys are especially sensitive to treatment with sodium metaarsenite); see WO 2003/086424, which is incorporated herein by reference;

solid tumor (eg, solid tumor of epithelial tissue; lymphoid tissue; connective tissue; bone; or central nervous system, such as neuroblastoma, retinoblastoma, glioblastoma, or oligodendroglioma); bone metastases; metastatic neoplastic disease (eg, cancer of lymphoid tissue, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, diffuse lymphoma, lymphoblastic lymphoma, large cell lymphoma or small cell lymphoma); primary or metastatic lung tumor; urogenital cancer such as prostate, bladder, kidney and testicular cancer; leukemia (eg, acute promyelocytic leukemia, acute myelogenous leukemia, and acute lymphoblastic leukemia); see WO 2006/121280, which is incorporated herein by reference;

pain (including pain due to cancer and pain not associated with cancer, such as visceral pain, postoperative or perioperative pain, central pain, chronic pain, neuropathic pain, back pain, pain associated with infectious disease, pain associated with surgical procedure, headache, burn, angina pectoris, herpetic neuralgia, dental condition, diabetic neuropathy, fibromyalgia, NSAID-resistant condition, somatoform disorders, cystitis, muscle damage, dysmenorrhea, osteoarthritis and stroke); inflammation (including non-cancer inflammation such as inflammation associated with asthma, pulmonary disease, autoimmune disease, arthritis, lupus, multiple sclerosis, Crohn's disease, ulcers

- 13 045346 colitis, chronic obstructive pulmonary disease and type I diabetes), autoimmune disorders and immunological disorders (for example, tissue rejection or organ rejection); diabetic retinopathy; diabetic vasculopathy; diabetic neuralgia; symptoms associated with insulitis, ulcerative colitis; see WO 2008/097824, which is incorporated herein by reference;

cancer, including cancer associated with cancer cells containing chromosomes having long telomeres (eg, lung cancer such as non-small cell lung cancer and prostate cancer); see WO 2009/120697, which is incorporated herein by reference;

blood cancer, metastatic cancer, cancer pain, or chronic pain.

3.7 Introduction with other means

In some embodiments, the pharmaceutical composition of the present invention may be used in combination with one or more other agents.

For example, the pharmaceutical composition of the present invention can be administered with other therapeutic agents such as analgesics, anesthetics, antianginal agents, antifungals, antibiotics, anticancer drugs (for example, non-arsenic anticancer drugs such as mitomycin C, cisplatin, paclitaxel and docetaxel ), anti-inflammatory drugs (eg, ibuprofen and indomethacin), anthelmintics, antidepressants, antidotes, antiemetics, antihistamines, antihypertensives, antimalarials, antimicrotubule drugs (eg, colchicine or vinca alkaloids), antimigraines, antimicrobials, antipsychotics , antipyretics, antiseptics, anti-signaling agents (eg, protein kinase C inhibitors or intracellular calcium mobilization inhibitors), antiarthritics, antithrombin agents, antituberculosis drugs, antitussives, antivirals, appetite suppressants, cardioactive drugs, chemical dependency drugs , laxatives, chemotherapeutic agents, coronary, cerebral or peripheral vasodilators, contraceptives, depressants, diuretics, expectorants, growth factors, hormonal agents, hypnotics, immunosuppressive agents, narcotic antagonists, parasympathomimetics, sedatives, stimulants, sympathomimetics, toxins ( eg cholera toxin), tranquilizers and medicines for urinary tract infections.

It should be understood that combined administration of a pharmaceutical composition of the present invention with one or more other agents may be simultaneous, sequential, or separate administration.

4. Method for preparing the pharmaceutical composition of the present invention

In a third aspect, the present invention provides a method for preparing a pharmaceutical composition according to the first aspect, the method comprising the following steps:

(a) mixing an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite with one or more pharmaceutically acceptable excipients to form a powder mixture, wherein the one or more pharmaceutically acceptable excipients is selected to minimize oxidation metaarsenite to metaarsenate;

(b) compressing the powder mixture obtained in step (a) to form a solid core; and (c) applying an enteric coating containing an enteric polymer to the solid core;

wherein the weight percentage of the enteric coating ranges from about 6% w/w. up to about 20% w/w based on the total weight of the pharmaceutical composition, and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

In a fourth aspect, the present invention provides a method for making a pharmaceutical composition according to the second aspect, comprising the following steps:

(a) mixing an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite with the following pharmaceutically acceptable excipients to form a powder mixture:

(i) a filler or diluent in the range of about 5 to 95% w/w, (ii) a disintegrant in the range of about 10 to 90% w/w, (iii) a glidant in the range of about 0.1 up to 5% w/w, (iv) lubricant in the range of about 0.1 to 5% w/w. and (v) optionally a binder in the range of from 0 to about 30% w/w;

(b) compressing the powder mixture obtained in step (a) to form a solid core;

(c) applying an enteric coating containing enteric acid to the solid core;

- 14 045346 strong polymer;

wherein the pharmaceutically acceptable excipients are selected to minimize the oxidation of metaarsenite to metaarsenate, wherein the weight percentage of the enteric coating is from about 6% w/w. up to about 20% w/w based on the total weight of the pharmaceutical composition, and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition.

In some embodiments of the method of the present invention, making the solid core does not involve adding water or solvent, i.e. No water or solvent is added during the manufacture of the solid core. Thus, in some embodiments, the mixing step (a) of the third and fourth aspects described above is performed without using water or a solvent, and the pressing step (b) of the third and fourth aspects described above is performed without using water or a solvent.

The pharmaceutical composition of the present invention can be manufactured by methods known in the art using standard equipment.

Generally, the pharmaceutical composition of the present invention can be prepared by mixing the ingredients of the composition (API and excipients) to form a mixed powder. Because the API concentration can be very low, a two- or three-step mixing process (using an API premix and a base mix) can be used to improve mixture uniformity. The length of mixing time may vary depending on the ingredients. The lubricant may be added at the same time as other ingredients to the main mixture or may be added at a later separate stage to avoid possible complications due to excessive lubrication (eg, decreased tablet hardness or problems associated with dissolution). Typically, the mixing step is carried out without the use of water or solvent, i.e. No water or solvent is added at the mixing stage. After mixing, the mixed powder is pressed to form a solid core. Typically the pressing step is carried out without the use of water or solvent, i.e. No water or solvent is added at the pressing stage. The solid core is then coated with an enteric polymer.

Thus, in some embodiments of the method of the present invention, the mixing step (step (a)) includes two steps: a first step comprising mixing the API (which is preferably passed through a mesh/sieve) with a portion of the excipient (and optionally the antioxidant) to form an API premix ; and a second step comprising mixing the glidant (which is preferably passed through a mesh/sieve), disintegrant, lubricant and optionally a binder with the API premix. In some embodiments, no water or solvent is used in the mixing step, that is, no water or solvent is added in the mixing step.

In some embodiments of the method of the present invention, the mixing step (step (a)) includes three steps: a first step comprising mixing the API (which is preferably passed through a mesh/sieve) with a portion of the excipient (and optionally the antioxidant) to form an API premix; a second step comprising mixing the glidant (which is preferably passed through a mesh/sieve), disintegrant and optionally a binder with the API premix to form a master mixture; and a third step of adding a lubricant (which is preferably passed through the screen along with a portion of the base mixture) to the base mixture and then mixing the resulting mixture. In some embodiments, no water or solvent is used in the mixing step, that is, no water or solvent is added in the mixing step.

A typical manufacturing method that uses a three-stage mixing step is described in more detail below. Typically, no water or solvent is used in the three-stage mixing step, i.e. no water or solvent is added during the three-stage mixing step.

The API is first passed through a screen (such as a hand screen). A premix containing API (API premix) is made by mixing sieved API with a portion of the filler. If one of the ingredients is an antioxidant, said antioxidant may be added to the API premix to ensure thorough mixing of the antioxidant with the API.

The glidant is passed through a sieve to deagglomerate. All other ingredients are then added, including the glidant, excluding the lubricant, with the API premix in the middle of the powder mass. The resulting mixture (main mix) is mixed to form a mixed powder (main blend).

The lubricant is sieved together with a small portion of the main mixture, and then the co-sifted mixture is added to the main mixture. This lubrication step can be performed separately to avoid possible complications due to excessive lubrication (eg, problems associated with decreased tablet hardness or dissolution).

- 15 045346

The resulting mixture is stirred to thereby form a powder mixture. Once mixed, the mixed powder is pressed to form a solid core.

In some embodiments, the hardness of the solid core is from about 50 N to about 200 N, such as from about 50 N to about 150 N, or from about 70 N to about 120 N. Typically, the target hardness level is at least about 80 N, preferably at least about 85 N, more preferably at least about 90 N, and most preferably at least about 100 N. In some embodiments, the hardness of the solid core is at least about 110 N.

In some embodiments, the hardness of the solid core is from about 80 N to about 115 N, such as about 85 N, about 90 N, about 95 N, about 100 N, about 105 N, or about 110 N. In some embodiments, the hardness of the hard core is at least about 50 N, at least about 55 N, at least about 60 N, at least about 65 N, at least about 70 N, at least about 75 N, at least about 80 N, at least about 85 N, at least about 90 N, at least about 95 N, at least about 100 N, at least about 105 N, at least about 110 N, at least about 115 N, according to at least about 120 N, at least about 125 N, at least about 130 N, at least about 135 N, at least about 140 N, at least about 145 N, at least about 150 N, at least at least about 155 N, at least about 160 N, at least about 165 N, at least about 170 N, at least about 175 N, at least about 180 N, at least about 185 N, at least about 190 N, at least about 195 N, or about 200 N. Preferably, the hardness of the solid core is at least about 85 N, more preferably at least about 90 N, even more preferably at least about 100 N, and most preferably at at least about 110 N. Typically, the hardness of the solid core does not exceed about 210 N.

Before applying the enteric coating, an intermediate layer can be applied to the solid core using polymers that are known in the art to be suitable for applying an intermediate layer.

The solid core is coated with an enteric coating, for example by spraying an enteric coating dispersion. The enteric coating dispersion can be made, for example, by dispersing the enteric coating polymer in deionized water or an organic solvent, mixing the dispersion and then passing through a sieve. The required amount or thickness of enteric coating on the solid core is achieved using standard methods known in the art, for example, by adjusting the spray rate of the enteric coating dispersion, adjusting the time that the solid cores remain in the coating pan, adjusting the inlet temperature, regulation of drum rotation speed or air pressure for spraying.

Examples

The present invention is further described below with reference to the following non-limiting examples.

Materials and methods

All materials used for the manufacture of the pharmaceutical compositions exemplified below were obtained from commercial sources.

Sodium meta-arsenite (SMA) was obtained from Sigma Aldrich Fine Chemicals. The resulting SMA active ingredient had very high purity (>98% As(III)) and minimal As(V) levels. In table 1 below shows the properties of the resulting active substance SMA.

Table 1. Properties of the obtained active ingredient SMA

Property Magnitude/Observation Appearance White to off-white powder Melting temperature 615D Solubility Approximately 950 mg/ml Typical analysis (As(III)) 98 - 99% Typical Purity Level (As(V)) <0.2% Typical water content < 1.0% G hygroscopicity (moisture absorption) ~ 40% at 75% air humidity (RH) >80% at 80% RH > 130% at 90% RH Density (true/particle) 2.1-2.3 g/cm ³

Materials listed below in table. 2 was used to prepare enteric-coated tablets containing 2.5 mg sodium metaarsenite (SMA). Where possible, higher density versions of the main excipients were selected to match the density of SMA (an inorganic material with an estimated true density of about 2.1-2.3 g/cm ^-3 which is very dense compared to most excipients).

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Table 2. List of materials

Materials Function Trade name/Supplier Sodium metaarsenite (“SMA”) (purity >98%) active pharmaceutical ingredient Sigma Aldrich Fine Chemicals (Madison, Wisconsin, USA) Calcium sulfate dihydrate filler Compactrol/JRS pharma Calcium carbonate filler PressCAL MD 92.5/JRS Calcium carbonate, premium grade filler Not applicable/JRS Dibasic calcium phosphate anhydrous filler Fujicalin/Fuji chemicals Dibasic calcium phosphate anhydrous, powder filler A Comprez/JRS pharma Dibasic calcium phosphate anhydrous, premium grade filler A-Comprez/JRS pharma High Density Silicated Microcrystalline Cellulose (sMCC) filler, compressible thinner Prosolv HD 90 High Density Microcrystalline Cellulose (MCC) binder Avicel PH302/FMC Partially pregelatinized starch binder, leavening agent, filler Lycatab C-LM/Roquette Partially pregelatinized starch binder, disintegrant, filler Starch 1500/Colorcon Hydroxypropyl cellulose binder Klucel EXF/Ashland L-Γ hydroxypropylcellulose binder, disintegrant LH-Bl/Shin-EtSu Colloidal silicon dioxide glidant Aerosil 200ZEvonik Sodium starch glycolate super baking powder Explotab/JRS Pharma Croscarmellose sodium super baking powder Ac-di-Sol/FMC Sodium stearyl fumarate lubricant PRUV/JRS pharma Opadryll (20А280013) sublayer Colorcon Acryl-EZE II White (493Z180022) coating polymer Colorcon

Equipment specified in table. 3 below was used to prepare and analyze enteric-coated compositions containing SMA.

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Table 3. List of equipment

Name of equipment Manufacturer Application Scales Sartorius weighing materials and tablets Mixer "Turbula" Turbula mixing 2L Mixer container "Turbula" Turbula mixing Density meter Copley density measurement Manesty F3 Single Punch Tablet Press Manesty making tablets Rotary tablet press (7 stations) SCI making tablets 6.5 mm Round Normal Biconcave NCCP Tools (plano-concave tooling) Natoli making tablets 0.25 inch tablet making machine Tooling Key International Key International making tablets Device for determining the strength of tablets Copley tablet strength measurement Micrometer Mitsuyi tablet thickness measurement Device for determining the abrasion of tablets Copley determination of tablet abrasion Disintegration Test Bath Copley disintegration test 15” Tablet coating machine Thai Coater coating

Manufacturing example 1.

Enteric-coated tablets of Formulation Examples 1.1-1.4 containing sodium metaarsenite (SMA) as the active pharmaceutical ingredient (API) were prepared according to the procedure described below.

In general, as detailed below, sodium metaarsenite (SMA) and excipients were mixed together (in a three-step mixing process without the use of water or solvent) to form a powder mixture. The powder mixture was then compressed to form a hard tablet core. An enteric coating was then applied to the solid tablet core.

Mixing

The following mixing process was used to mix the ingredients.

The API and other ingredients for the composition were measured and weighed. Since the API concentration is very low, a three-step mixing process (using API premix and base mix) was used to improve the homogeneity of the mixture.

The API was passed through a 200 µm sieve (hand sieve). Sifting time was 5-8 minutes.

A premix containing API (API premix) was prepared by mixing screened API with a few grams (20g for 500g and 30g for 700g batches) of filler in a suitable container (100ml container for 500g and 150g batches). ml for a batch size of 700 g) for 10 min at 49 rpm using a Turbula mixer.

The glidant (colloidal silica) was passed through a 500 μm sieve to deagglomerate. All other measured ingredients, including the sifted glidant, excluding the lubricant (sodium stearyl fumarate), were then added to a 2 L glass Turbula container, with the API premix placed in the middle of the powder mass.

The resulting mixture (master mix) was mixed for about 10 to about 20 minutes at 49 rpm using a Turbula mixer to form a mixed powder (master mix).

The lubricant (sodium stearyl fumarate) was co-screened with a small portion of the base mixture using a 500 μm sieve, and the co-screened mixture was then added to the base mixture. This lubrication step was performed separately to avoid possible complications due to excessive lubrication (eg, problems associated with decreased tablet hardness or dissolution).

The resulting mixture was stirred for 2 minutes at 49 rpm in a Turbula mixer to thereby form a powder mixture. The flow properties of the powder mixture were assessed.

Pressing

The powder mixture was compressed on a Manesty F3 single punch tablet press using 6.5 mm conventional concave plano (NCCP) tooling to a target tablet weight of 150 mg. Manesty F3 only has arbitrary units (AU) for compression force, and it is not possible to directly measure the applied force. The target hardness level was above 90 N.

Enteric coating

An enteric coating dispersion with a solid content of 20% w/w. prepared by dispersing Acryl-EZE II White (493Z180022) in deionized water. The dispersion was mixed on a paddle mixer for 45 minutes before use and throughout the coating process. Before use, the dispersion was passed through a 250 μm sieve.

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The 15 Coating Pan (Thai Coater) was left to equilibrate to the desired temperature before loading the solid tablet cores. Due to the small batch size, fillers were added to the API solid cores to meet the loading requirements of the casing machine. The solid tablet cores were left to equilibrate in the dryer for 10 minutes before coating. The same temperature and air flow were used for the heating, coating and drying steps. The coated tablets were dried for 10 minutes in the dryer after coating. Samples were collected after weight gain of 8, 10 and 12% w/w.

Dissolution studies

Dissolution studies were carried out using 500 ml of medium and USP Method 2 (paddles) initially with a paddle speed of 100 rpm. One set of six enteric-coated tablets was tested (n = 6). Samples of the dissolution medium were taken after 2 hours in acid and sodium metaarsenite levels were determined to assess gastric acid resistance. The medium was replaced with phosphate buffer at pH 6.8 and samples were taken at 15 min intervals to obtain dissolution profiles.

This method is based on the pharmacopoeial method for enteric dosage forms (EP.2.9.3 and USP <711>), as shown in the table below. 4.

Table 4. Dissolution Test Conditions

Stage 1 Conditions 0.01M HC1 Description Acid phase Target Acid resistance Requirement No more than 10% released after 2 hours 2 pH 6.8 Buffer Profile Usually at least 75% phosphate buffer phase release in 30 -45 minutes

Recipe example 1.1.

A solid pharmaceutical composition (P63) containing sodium metaarsenite (SMA) as an active pharmaceutical ingredient (API) was prepared using the method described above in Manufacturing Example 1.

The composition was prepared in an amount of 700 g. Samples having homogeneity of mixture and homogeneity of composition were selected for homogeneity assessment after a basic mixing time of 20 minutes.

In table 5 below shows the composition of a hard core tablet containing 2.53 mg of sodium metaarsenite (before the coating step). (Table 5.1 below shows another possible hard core tablet composition containing 2.50 mg sodium metaarsenite (before the coating step).

Table 5. Composition of P63 tablet hard core

Material Function mg/tablet % w/w Sodium metaarsenite API 2.53 1.69 Dibasic Anhydrous Calcium Phosphate (A-Comprez Fine Granules) filler 82.22 54.81 L-Γhydroxypropylcellulose (grade LH-B1) binder, disintegrant 60.00 40.00 Hydroxypropyl cellulose (Klucel EXF) binder 3.00 2.00 Colloidal silicon dioxide (Aerosil 200) glidant 0.75 0.50 Sodium stearyl fumarate (PRUV) lubricant 1.50 1.00 Total 150.00 100.00

After the mixing stage, the powder mixture showed good flow properties, as indicated by the Carr index (29.3%). The powder mixture before pressing had the following properties: loose density: 0.64 g/cm ³ , bulk density after compaction: 0.91 g/cm ³ , Carr index: 29.3%, Hausner ratio: 1.30.

The powder mixture compressed very well and no mass deviations and/or visual segregation were observed during the experiment. High tablet hardness (104.8 N) and low friability (0.08%) were achieved, and the disintegration time (34 seconds) was relatively fast. The average tablet hard core thickness was 3.63 mm.

Blend homogeneity samples were collected after mixing for 20 minutes, and blend uniformity samples were collected at the beginning, middle, and end of the pressing cycle. Mixture homogeneity results showed excellent homogeneity with a % relative standard deviation (RSD) value of 1.3. The compositional uniformity of the tablet hard cores throughout the compression cycle (start, middle and end) showed good homogeneity as a maximum acceptable value (AV) < 7.4 was achieved (AV value < 15 is acceptable).

After the compression step, the hard tablet core was coated with the Acryl-EZE II White (493Z180022) enteric coating polymer system, which was manufactured as described in Manufacturing Example 1. The coating parameters are shown in Table 1 below. 6.

Table 6. Coating parameters

Parameter Result Coating plant 15" Thai Coater Inlet temperature 90-110°С Outlet temperature ~50°С Drum rotation speed 16 rpm Spray speed 10-11 g/min Layer temperature ~35°С Inlet and outlet dampers Both in the middle Distance between gun - 5 cm (Partitions are not visible) spray and layer Liquid nozzle (mm) 1.2 mm Air flow pressure 20 psi ² Spray gun air pressure 10 psi ² Filler weight (g) 2500.0 g Weight of active tablets (g) 473.0 g Weight of tablet layer (g) 2973.0 g Initial weight of 20 tablets (g) 3.017 g Target weight gain for coating 12% 3.379 g (G) Weight 20 tablets after weight gain 3.381 g 12% (g) (weight gain 12.06%)

The enteric-coated tablet showed an acceptable dissolution profile (medium 500 ml, paddle speed 100 rpm). After 120 min, the composition remained unchanged in an acidic environment (pH 1.0) with the release of 0% API. After 135 minutes at pH 6.8, 91% of the API was released. After 150 min at pH 6.8, 98% of the API was released. After 165 min at pH 6.8, 100% of the API was released.

The enteric-coated tablet demonstrated satisfactory resistance to gastric acid and met the proposed preliminary requirements of at least 75% release in 45 minutes for enteric-coated dosage forms.

In table 5.1 below shows another possible composition of a hard core tablet containing 2.50 mg of sodium metaarsenite (before the coating step). Solid core containing the components described in table. 5.1 can be manufactured in a manner similar to that described above for a solid core having the components described in table. 5.

Table 5.1, Alternative P63 Tablet Core Composition

Material Function mg/tablet % w/w Sodium Mataarsenite API 2.50 1.67 Dibasic calcium phosphate, anhydrous (A-Comprez fine granules) filler 82.25 54.83 L-Γhydroxypropylcellulose (grade LH-B1) binder, disintegrant 60.00 40.00 Hydroxypropyl cellulose (Klucel EXF) binder 3.00 2.00 Colloidal silicon dioxide (Aerosil 200) glidant 0.75 0.50 Sodium stearyl fumarate (PRUV) lubricant 1.50 1.00 Total 150.00 100.00

Recipe example 1.2.

A solid pharmaceutical composition (P23) containing sodium metaarsenite (SMA) as an active pharmaceutical ingredient (API) was prepared using the method described above in Manufacturing Example 1.

The composition was prepared in an amount of 500 g. Samples for testing the homogeneity of the mixture were taken after 10, 15 and 20 minutes of the main mixing time. The mixture was compressed to form a hard tablet core, and then the hard tablet core was coated.

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In table 7 below shows the composition of a hard core tablet containing 2.50 mg of sodium metaarsenite (before the coating step).

Table 7. Composition of the solid core of the P23 tablet

Material Function mg/tablet % w/w Sodium metaarsenite API 2.50 1.67 Dibasic calcium phosphate, anhydrous, powder (AComprez powder) filler 37.50 25.00 Partially pregelatinized starch (Starch 1500) binder, leavening agent, filler 45.00 30.00 Dibasic calcium phosphate, anhydrous, granules (Fujicalin) filler 58.25 38.83 Sodium starch glycolate (Explotab) super baking powder 4.50 3.00 Colloidal silicon dioxide (Aerosil 200) glidant 0.75 0.50 Sodium stearyl fumarate (PRUV) lubricant 1.50 1.00 Total 150.00 100.00

After the mixing step, the powder mixture showed good flow properties as indicated by the Carr index (26.37%). The powder mixture before pressing had the following properties:

loose density: 0.67 g/cm ³ , bulk density after compaction: 0.91 g/cm ³ , Carr index: 26.37%, Hausner ratio: 1.36, angle of repose: 24.32°.

Samples for testing the homogeneity of the mixture were taken after mixing for 10, 15 and 20 minutes of the main mixing time. The composition showed good homogeneity with a mixing time of 20 minutes.

Compression was performed on a Manesty F3 single-punch tablet press using NCCP 6.5 mm tooling. The average hardness of the solid core was 94.3 N, the average thickness was 3.62 mm, the abrasion rate was 0.33% and the disintegration time was 39 s.

The mass of the hard cores was constant throughout the pressing cycle and suitable hard cores were produced. No visual segregation was observed. Samples (10 solid cores in duplicate) were collected at the beginning, middle and end of the pressing cycle and submitted for composition uniformity testing.

After the compression step, the hard tablet core was coated with the Acryl-EZE II White enteric coating polymer system (493Z180022), which was manufactured as described in Manufacturing Example 1, and samples were collected after weight gain of 8, 10 and 12% w/w. Coating parameters are shown in the table below. 8.

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Table 8. Coating parameters

Parameter Result Coating plant Thai Coater Inlet temperature 81 -90°С Outlet temperature ~50°С Drum rotation speed 18 rpm reduced to 16 rpm Initial Spray Speed 7 g/min Spray rate after 30 min 11 g/min Layer temperature ~35°С Inlet and outlet dampers Both in the middle Distance between spray gun and layer 5 cm (Partitions are not visible) Pump speed 05 Liquid nozzle (mm) 1.2 mm Air flow pressure 10 psi ² Spray gun air pressure 20 psi ² Filler weight (g) 3000 g Weight of active tablets (g) 240 g Weight of tablet layer (g) 3240 g Initial weight of 20 tablets (g) 3.015 g Target % w/w for tablet coating 8% Target weight gain for coating 8% (g) 3.256 g Amount of dispersion sprayed to achieve a weight gain of 8% (g) 1900 g Weight of 20 tablets after weight gain of 8% (g) 3.248 g Target % w/w for tablet coating 10% Target weight gain for coating 10% (g) 3.317 g Amount of dispersion sprayed to achieve a weight gain of 10% (g) 2400 g Weight of 20 tablets after weight gain of 10% (g) 3.328 g Target % w/w for tablet coating 12% Target weight gain for coating 12% (g) 3.377 g Amount of dispersion sprayed to achieve a weight gain of 12% (g) 2900 g Weight of 20 tablets after weight gain of 12% (g) 3.384 g

Enteric-coated tablets with weight gain of 8, 10 and 12% w/w. subjected to a dissolution test (500 ml dissolution medium, paddle speed 75 rpm) to determine appropriate levels of enteric coating. The dissolution results are presented in the table below. 9.

Table 9. Dissolution test results

Sample name Average value (% drug release) Time (min) 120 135 150 165 195 Wednesday pH 1.0 pH 6.8 pH 6.8 pH 6.8 pH 6.8 enteric coated tablets 8% w/w. 00 67 80.5 87 90 enteric coated tablets 10% w/w. 00 26 82 89 undefined enteric coated tablets 12% w/w. 00 27 83 90 92

The enteric-coated tablets remained unchanged in acidic conditions after 120 min. The enteric-coated tablets demonstrated satisfactory resistance to gastric acid and met the proposed preliminary requirements of no more than 75% release in 45 minutes for enteric-coated dosage forms.

Based on the dissolution test results, it was found that 12% w/w. was the optimal increase in coating mass.

Recipe example 1.3.

A solid pharmaceutical composition (RP1) containing sodium metaarsenite (SMA) as an active pharmaceutical ingredient (API) was prepared using the method described in Manufacturing Example 1 above.

The composition was prepared in an amount of 500 g. Samples for testing the homogeneity of the mixture were taken after 10, 15 and 20 minutes of the main mixing time. The mixture was compressed to form a hard tablet core and then the hard tablet core was coated. L-hydroxypropylcellulose (L-HPC; low-substituted hydroxypropylcellulose grade LH-B1) was used because it acts as a binder and disintegrant. Since L-HPC is insoluble in water, it was expected that it would provide solid tablets.

In table 10 below shows the composition of a hard core tablet containing 2.50 mg of sodium metaarsenite (before the coating step).

Table 10. Composition of P31 tablet hard core

Material Function mg/tablet % w/w Sodium metaarsenite API 2.50 1.67 Dibasic calcium phosphate, anhydrous, powder (AComprez powder) filler 37.50 25.00 Dibasic calcium phosphate, anhydrous, granules (Fujicalin) filler 80.75 53.83 L-Hydroxypropylcellulose (grade LH-B1) binder, disintegrant 22.50 15.00 Sodium starch glycolate (Explotab) super baking powder 4.50 3.00 Colloidal silicon dioxide (Aerosil 200) glidant 0.75 0.50 Sodium stearyl fumarate (PRUV) lubricant 1.50 1.00 Total 150.00 100.00

After the mixing step, the powder mixture showed good flow properties as indicated by the Carr index (23.68%). The powder mixture before pressing had the following properties: loose density: 0.58 g/ ^cm3 , bulk density after compaction: 0.76 g/ ^cm3 , Carr index: 23.68%, Hausner ratio: 1.31, angle natural slope: 27.96°.

Samples for mixture homogeneity testing were taken after mixing for 10, 15 and 20 min of the main mixing time. The composition showed good homogeneity with a mixing time of 20 minutes.

Compression was performed on a Manesty F3 single-punch tablet press using NCCP 6.5 mm tooling. The average hardness of the solid core was 104.3 N, the average thickness was 3.52 mm, the abrasion rate was 0.23% and the disintegration time was 30 s.

The mass of the hard cores was constant throughout the pressing cycle and suitable hard cores were produced. No visual segregation was observed. Samples (10 solid cores in duplicate) were collected at the beginning, middle and end of the pressing cycle and submitted for composition uniformity testing.

After the compression step, the hard tablet core was coated with the Acryl-EZE II White enteric coating polymer system (493Z180022), which was manufactured as described in Manufacturing Example 1, and samples were collected after 8, 10, and 12% w/w weight gain. Coating parameters are shown in the table below. eleven.

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Table 11. Coating parameters

Coating plant Thai Coater Inlet temperature 81 - 90°С Outlet temperature 50°С Drum rotation speed 18 rpm reduced to 16 rpm Initial Spray Speed 7 g/min Spray rate after 30 min And g/min Layer temperature 35°С Inlet and outlet dampers Both in the middle Distance between spray gun and layer 5 cm (Partitions are not visible) Pump speed 05 Liquid nozzle (mm) 1.2 mm Air flow pressure 10 psi ² Spray gun air pressure 20 psi ² Filler weight (g) 3000 g Weight of active tablets (g) 260 g Weight of tablet layer (g) 3260 g Initial weight of 20 tablets (g) 2.995 g Target % w/w tablet coating 8% Target weight gain for 8% coverage (g) 3.235 g Amount of dispersion sprayed to achieve a weight gain of 8% (g) 1900 g Weight of 20 tablets after weight gain of 8% (g) 3.231 g Target % w/w tablet coating 10% Target weight gain for 10% coverage (g) 3.295 g Amount of dispersion sprayed to achieve 10% weight gain (g) 2400 g Weight of 20 tablets after weight gain of 10% (g) 3.282 g Target % w/w tablet coating 12% Target weight gain for 12% coverage (g) 3.354 g Amount of dispersion sprayed to achieve 12% weight gain (g) 2900 g Weight of 20 tablets after weight gain of 12% (g) 3.362 g

Enteric-coated tablets with weight gain of 8, 10 and 12% w/w. subjected to a dissolution test (500 ml dissolution medium, paddle speed 75 rpm) to determine appropriate levels of enteric coating. The dissolution results are presented in the table below. 12.

Table 12. Dissolution test results

Sample name Average value (% drug release) Time (min) 120 135 150 165 195 Wednesday pH 1.0 pH 6.8 pH 6.8 pH 6.8 pH 6.8 enteric coated tablets 8% w/w. 19.6 0* 0* 0* 0* enteric coated tablets 10% w/w. 00 55 74 86 undefined enteric coated tablets 12% w/w. 00 67 81 88 91

* All tablets are destroyed by acid. 0% of the drug was dissolved in the pH 6.8 medium since broken tablets would lead to degradation in the acid stage and hence no API was detected in the buffer stage.

Enteric-coated tablets with 8% weight gain failed the acid resistance test. The 10% weight gain enteric-coated tablets and the 12% weight gain enteric-coated tablets demonstrated satisfactory gastric acid resistance and met the proposed preliminary release specifications of at least 75% in 45 minutes for the enteric-coated dosage forms.

Based on the dissolution results obtained, it was found that 12% w/w. is the optimal increase in coating mass.

Recipe example 1.4.

A solid pharmaceutical composition (P66) containing sodium metaarsenite (SMA) as an active pharmaceutical ingredient (API) was prepared using the method described

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The composition was prepared in quantities of 700 g. Mixture homogeneity test samples and composition homogeneity test samples were taken to assess homogeneity after a basic mixing time of 20 minutes.

In table 13 below shows the composition of a hard core tablet containing 2.53 mg of sodium metaarsenite (before the coating step).

Table 13. Composition of P66 tablet hard core

Material Function mg/tablet % w/w Sodium metaarsenite API 2.53 1.69 Dibasic calcium phosphate anhydrous (A-Comprez fine granules) filler 71.55 47.70 Partially pregelatinized starch (Starch 1500) binder, leavening agent, filler 67.67 45.11 Sodium starch glycolate (Explotab) super baking powder 6.00 4.00 Colloidal silicon dioxide (Aerosil 200) glidant 0.75 0.50 Sodium stearyl fumarate (PRUV) lubricant 1.50 1.00 Total 150.00 100.00

After the mixing step, the powder mixture showed good flow properties as indicated by the Carr index (25.74%). The powder mixture before pressing had the following properties:

loose density: 0.75 g/cm ³ , bulk density after compaction: 1.01 g/cm ³ , Carr index: 25.74%, Hausner ratio: 1.35.

The powder mixture compressed very well and no change in mass and/or visual segregation was observed during the experiment. High hard core hardness (87.4 N) and low abrasion (0.11%) were achieved, and the disintegration time (2 min 52 s) was relatively fast. The average thickness of the solid core was 3.66 mm.

Blend homogeneity test samples were collected after mixing for 20 minutes, and blend homogeneity test samples were collected at the beginning, middle, and end of the pressing cycle. Mix homogeneity test results showed excellent homogeneity with a relative standard deviation (RSD) value of 2.1. The test results for homogeneity of solid core composition throughout the entire pressing cycle (start, middle and end) showed good homogeneity as a maximum acceptable value (AV) < 6.3 was achieved (AV value < 15 is acceptable).

After the compression step, the hard tablet core was coated with the Acryl-EZE II White enteric coating polymer system (493Z180022), which was manufactured as described in Manufacturing Example 1. The coating parameters are shown in Table 1 below. 14.

Table 14. Coating parameters

Parameter Result Coating plant 15" Thai Coater Inlet temperature 90-110°С Outlet temperature ~50°С Drum rotation speed 16 rpm Initial Spray Speed 10-11 g/min Bed temperature Inlet and outlet dampers Distance between spray gun and layer Liquid nozzle (mm) Air flow pressure Gun air pressure Fill weight (g) ~35°C Both in the middle 5 cm (Partitions not visible) 1.2 mm 20 lb/in ² 10 lb/in ² 2600 g Weight of active tablets (g) 350 g Weight of tablet layer (g) 2950.0 g Initial weight of 20 tablets (g) 3.010 g Target weight gain for 12% coverage (g) 3.371 g Weight of 20 tablets after increasing weight by 12% (g) 3,380 g (12.2% weight increase)

The enteric-coated tablet showed an acceptable dissolution profile (medium 500 ml, paddle speed 100 rpm). After 120 min, the composition remained unchanged in an acidic environment (pH 1.0) with the release of 0% API. After 135 minutes at pH 6.8, 21% of the API was released. After 150 min at pH 6.8, 86% of the API was released. After 165 min at pH 6.8

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The enteric-coated tablet demonstrated satisfactory resistance to gastric acid and met the proposed release requirement of at least 75% in 45 minutes for enteric-coated dosage forms.

Manufacturing example 2.

In table 15 below shows the composition of an enteric-coated tablet containing 2.5 mg of sodium metaarsenite as an active pharmaceutical ingredient (API). Enteric-coated tablets were prepared using the method described below.

Table 15. Composition of enteric-coated tablets according to manufacturing example 2

Materials Function mg/tablet % w/w Sodium metaarsenite (SMA) API 2.50 1.67 Dibasic calcium phosphate, anhydrous, USP (powder) thinner, filler 37.50 25.00 Silicated microcrystalline cellulose (Prosolv HD90) filler, compressible thinner 107.00 71.33 Sodium starch glycolate (Explotab) super ripper 1.50 1.00 Colloidal Silicon Dioxide (Cab-o-sil) glidant 0.75 0.50 Sodium stearyl fumarate (PRUV) lubricant 0.75 0.50 Total - core: 150.00 100 Enteric coating polymer Acryl-EZE Green (93011863) Enteric coating 16.50 Total - as a coated tablet: 166.50

In general, as detailed below, sodium metaarsenite (SMA) and excipients were mixed together (a two-step mixing process without the use of water or solvent) to form a powder mixture. The powder mixture was then compressed to form a hard tablet core. An enteric coating was then applied to the solid tablet core.

Mixing

The following mixing process was used to mix the ingredients.

The API and other ingredients for the composition were measured and weighed. Since the API concentration was very low, a two-step mixing process (using an API premix and a base mix) was used to achieve improved mixture uniformity.

The API was passed through a 106 µm sieve (sieve time approximately 5-8 min).

A portion of the dibasic calcium phosphate was added to the sieved API and the resulting mixture was stirred for 30 minutes to form the API premix.

The API premix was then mixed with the remaining dibasic calcium phosphate and other excipients (silicated microcrystalline cellulose, sodium starch glycolate, colloidal silica and sodium stearyl fumarate) to form the master mix. The main mix was stirred using an intensifier rod for 4 minutes to obtain a powder mixture.

Pressing

The powder mixture was compressed on a Key International tablet machine using 0.25 inch tooling to a target tablet weight of 150 mg ± 5% (range 142.5-157.5 mg). The solid cores were cleaned of dust.

The final hard cores showed no significant abrasion (0.00%) and the hardness was 156.9 N (16 kgf).

Enteric coating

An enteric coating dispersion with a solid content of 25% w/w. were prepared by dispersing undried Acryl EZE powder in deionized water. The dispersion was stirred for about 30 minutes (until homogeneous).

The dispersion was applied to the dust-free solid cores by spraying (350 g/min) with a weight gain of approximately 10-12% w/w. The drum rotation speed was about 6-8 rpm. The coated tablets were dried after coating.

It should be understood that if reference is made in this document to any publication

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Claims (25)

prior art, such reference does not constitute an admission that this publication is part of the generally known knowledge in the field, in Australia or any other country. In the following claims and the preceding description, unless the context otherwise requires by linguistic expression or necessary implementation, the word contain or variations such as contains or containing is used in an inclusive sense, i.e. to indicate the presence of specified features, but without excluding the presence or addition of other features in various embodiments of the invention. CLAIM 1. Pharmaceutical composition, which is a coated tablet or capsule containing: (a) a solid core containing sodium metaarsenite or potassium metaarsenite and the following pharmaceutically acceptable excipients: (i) a filler or diluent ranging from about 5 to 95% w/w. from the solid core, wherein the filler or diluent is selected from dibasic anhydrous calcium phosphate, partially pregelatinized starch, silicated microcrystalline cellulose, microcrystalline cellulose, calcium sulfate dihydrate, lactose, hydrogen calcium phosphate, calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate or a mixture thereof ; (ii) a leavening agent in the range of about 10 to 90% w/w. from the hard core, wherein the disintegrant is selected from L-hydroxypropylcellulose, partially pregelatinized starch, crospovidone, potato starch, corn starch, sodium starch glycolate and alginic acid; (iii) a glidant in the range of about 0.1 to 5% w/w. from the solid core, wherein the glidant is selected from colloidal silicon dioxide and talc; and (iv) a lubricant in the range of about 0.1 to 5% w/w. from the solid core, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, stearic acid, talc, and silicon dioxide; and (b) an enteric coating comprising an enteric polymer, wherein the enteric polymer is selected from copolymers of acrylic acids and their esters or methacrylic acids or their esters, cellulose acetate phthalate polymers, hydroxypropyl methylcellulose phthalate polymers, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and trimellitate cellulose acetate; while the enteric coating provides a weight gain of approximately 9.5% wt./wt. from solid core to approximately 14% w/w. from the solid core, and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition. 2. The pharmaceutical composition according to claim 1, characterized in that the amount of sodium metaarsenite or potassium metaarsenite in the solid core is approximately 0.1-5.0% wt./wt. from the hard core. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that the solid core contains sodium metaarsenite. 4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the filler or diluent is present in the solid core of the pharmaceutical composition in an amount from about 10 to 90% wt./wt. from the solid core and/or the filler or diluent is selected from anhydrous dibasic calcium phosphate, partially pregelatinized starch, silicated microcrystalline cellulose, microcrystalline cellulose, lactose, calcium hydrogen phosphate, calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate or a mixture thereof. 5. The pharmaceutical composition according to claim 4, characterized in that the filler or diluent is anhydrous dibasic calcium phosphate, partially pregelatinized starch, or a mixture thereof. 6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the disintegrant is present in the solid core of the pharmaceutical composition in an amount from about 10 to 50% wt./wt. from the hard core and/or the disintegrant is selected from L-hydroxypropylcellulose, partially pregelatinized starch, potato starch, corn starch, sodium starch glycolate and alginic acid. 7. The pharmaceutical composition according to claim 6, characterized in that the disintegrant is L-hydroxypropylcellulose, partially pregelatinized starch, sodium starch glycolate or a mixture of two or more of them. 8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the glidant is present in the solid core of the pharmaceutical composition in an amount of from about 0.3 to 4.0% - 27 045346 wt./wt. from the solid core and/or the glidant is colloidal silicon dioxide. 9. Pharmaceutical composition according to claim 8, characterized in that the glidant is colloidal silicon dioxide. 10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that the lubricant is present in the solid core of the pharmaceutical composition in an amount of from about 0.3 to 4.0% wt./wt. from the hard core and/or the lubricant is selected from sodium stearyl fumarate, magnesium stearate, stearic acid and silicon dioxide. 11. Pharmaceutical composition according to claim 10, characterized in that the lubricant is sodium stearyl fumarate. 12. Pharmaceutical composition according to any one of claims 1 to 11, characterized in that it additionally contains a binder in an amount of from about 1 to 30% wt./wt. from the hard core 13. The pharmaceutical composition according to claim 12, characterized in that the binder is selected from silicated microcrystalline cellulose, microcrystalline cellulose, partially pregelatinized starch, L-hydroxypropylcellulose (low-substituted hydroxypropylcellulose), hydroxypropylcellulose, copovidone (polyvinylpyrrolidone), pregelatinized corn starch, hydroxypropylmethylcellulose , starch , gum arabic, corn starch and gelatin. 14. Pharmaceutical composition according to claim 12 or 13, characterized in that the binder is L-hydroxypropylcellulose (low-substituted hydroxypropylcellulose), a mixture of L-hydroxypropylcellulose (low-substituted hydroxypropylcellulose) and hydroxypropylcellulose or partially pregelatinized starch. 15. Pharmaceutical composition according to any one of claims 1-14, characterized in that the enteric coating provides a weight gain of approximately 10% wt./wt. from solid core to approximately 14% w/w. from the solid core and/or the enteric coating polymer is selected from copolymers of acrylic acids and their esters or methacrylic acids or esters thereof, cellulose acetate phthalate polymers, hydroxypropyl methylcellulose phthalate polymers, hydroxypropyl methylcellulose acetate succinate and cellulose acetate trimellitate. 16. Pharmaceutical composition according to claim 15, characterized in that the enteric coating polymer is a copolymer of methacrylic acid and ethyl acrylate (1:1). 17. The pharmaceutical composition according to any one of claims 1 to 16, characterized in that the solid core is selected from a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate, L-hydroxypropylcellulose, hydroxypropylcellulose, colloidal silicon dioxide and sodium stearyl fumarate; a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate powder, partially pregelatinized starch, anhydrous dibasic calcium phosphate, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate; a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate powder, anhydrous dibasic calcium phosphate, L-hydroxypropylcellulose, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate; a hard core containing sodium metaarsenite, anhydrous dibasic calcium phosphate, partially pregelatinized starch, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate; and a solid core containing sodium metaarsenite, anhydrous dibasic calcium phosphate, silicated microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and sodium stearyl fumarate. 18. Pharmaceutical composition according to any one of claims 1 to 16, characterized in that the pharmaceutical composition is an enteric-coated tablet containing 1.67% wt./wt. sodium metaarsenite from the solid core and having a solid core diameter of approximately 6.5 mm, a solid core weight of 150 mg and an enteric coating that adds about 12% w/w. from the hard core. 19. Use of a pharmaceutical composition according to any one of claims 1 to 18 for the treatment of a disease or condition which is selected from solid malignancy, metastatic bone lesion, metastatic neoplastic disease, primary or metastatic lung tumor, urogenital cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disorders, immunological disorders, diabetic retinopathy, diabetic vasculopathy, diabetic neuralgia, symptoms associated with insulitis, and ulcerative colitis. 20. A method for manufacturing a pharmaceutical composition according to any one of claims 1 to 18, including the following steps: - 28 045346 (a) mixing an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite with the following pharmaceutically acceptable excipients to form a powder mixture to obtain a solid core: (i) a filler or diluent ranging from about 5 to 95% w/w. solid core, wherein the filler or diluent is selected from dibasic anhydrous calcium phosphate, partially pregelatinized starch, silicated microcrystalline cellulose, microcrystalline cellulose, calcium sulfate dihydrate, lactose, hydrogen calcium phosphate, calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate or a mixture thereof, (ii) a leavening agent in the range of about 10 to 90% w/w. from the hard core, wherein the disintegrant is selected from L-hydroxypropylcellulose, partially pregelatinized starch, crospovidone, potato starch, corn starch, sodium starch glycolate and alginic acid, (iii) glidant in the range of about 0.1 to 5% wt./ wt. from the solid core, wherein the glidant is selected from colloidal silica and talc, (iv) a lubricant in the range of about 0.1 to 5% w/w. a solid core and wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, stearic acid, talc and silicon dioxide; (b) compressing the powder mixture formed in step (a) to form a solid core; and (c) applying to the solid core an enteric coating containing an enteric polymer, wherein the enteric polymer is selected from copolymers of acrylic acids and their esters or methacrylic acids, or their esters, cellulose acetate phthalate polymers, hydroxypropyl methylcellulose phthalate polymers, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and cellulose acetate trimellitate; while the enteric coating provides a weight gain of approximately 9.5% wt./wt. from solid core to approximately 14% w/w. from the solid core and wherein the thickness of the coating is from about 6.5 to about 15% of the thickness of the pharmaceutical composition. 21. The method according to claim 20, in which step (a) includes two stages: (i) mixing the API with a portion of the excipient to form an API premix; and (ii) mixing a glidant, a disintegrant, a lubricant, and optionally a binder with the API premix, wherein the glidant is present in the range of 0 to about 30% w/w. from a hard core; wherein the glidant is selected from silicated microcrystalline cellulose, microcrystalline cellulose, partially pregelatinized starch, L-hydroxypropylcellulose (low-substituted hydroxypropylcellulose), hydroxypropylcellulose, copovidone (polyvinylpyrrolidone), pregelatinized corn starch, hydroxypropyl methylcellulose, starch, acacia gum, corn starch, and Latina 22. The method according to claim 20, in which step (a) includes three stages: (i) mixing the API with a portion of the excipient to form an API premix; (ii) mixing the glidant, disintegrant, and optionally a binder with the API premix, wherein the glidant is present in the range of 0 to about 30% w/w. from a hard core; wherein the glidant is selected from silicated microcrystalline cellulose, microcrystalline cellulose, partially pregelatinized starch, L-hydroxypropylcellulose (low-substituted hydroxypropylcellulose), hydroxypropylcellulose, copovidone (polyvinylpyrrolidone), pregelatinized corn starch, hydroxypropyl methylcellulose, starch, acacia gum, corn starch, and Latin; and then (iii) adding a lubricant that was optionally mixed with a portion of the mixture from step (ii), and then mixing. 23. A method according to any one of claims 20 to 22, wherein step (a) and/or step (b) does not involve adding water or a solvent. 24. A method of treating a disease or condition of a subject, comprising orally administering to the subject a pharmaceutical composition according to any one of claims 1 to 18, where the disease or condition is selected from solid malignancy, metastatic bone disease, metastatic neoplastic disease, primary or metastatic lung tumor, urogenital cancer , leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disorders, immunological disorders, diabetic retinopathy, diabetic vasculopathy, diabetic neuralgia, symptoms associated with insulitis, and ulcerative colitis. 25. The use of a pharmaceutical composition according to any one of claims 1 to 18 for the manufacture of an oral medicament for the treatment of a disease or condition, wherein the disease or condition is selected from solid malignancy, metastatic bone disease, me- - 29 045346 tastatic neoplastic disease, primary or metastatic lung tumor, urogenital cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disorders, immunological disorders, diabetic retinopathy, diabetic vasculopathy, diabetic neuralgia, symptoms associated with insulitis, and ulcerative colitis. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2