TW202034930A - Pharmaceutical composition and method of manufacture - Google Patents

Abstract

The present application relates to pharmaceutical compositions comprising a salt of arsenous acid and methods of manufacturing the pharmaceutical compositions.

Description

Pharmaceutical composition and manufacturing method

The present invention relates to a pharmaceutical composition containing sodium or potassium metaarsenite, and a method for manufacturing the pharmaceutical composition. The present invention also relates to a treatment method using the pharmaceutical composition.

Cancer is a significant health problem in the world. Although there have been advances in cancer detection and treatment, there are currently no vaccines or other methods that can be successfully prevented or treated in general. The management of the disease currently relies on early diagnosis combined with active treatment, which can include one or more of various therapies, such as surgery, radiation therapy, chemotherapy and hormone therapy. Even though these therapies provide benefits to many patients, high mortality rates continue to be observed in many cancers. The development of improved anti-tumor agents will promote cancer prevention and treatment.

Unfortunately, cancer is the leading cause of death for both men and women, second only to heart disease. In fighting cancer, many technologies have been developed and are the subject of current research, which involve understanding the nature and causes of diseases and providing methods to control or cure the diseases.

Although thousands of possible anticancer drugs have been evaluated, the treatment of human cancer is still full of complications, which often presents a series of sub-optimal treatment options. Therefore, chemotherapeutic agents, which have little or no toxicity, are inexpensive to obtain or manufacture, are well tolerated by patients, and are easy to administer, will be an ideal supplement to the treatment modalities currently available to oncologists. It is also hoped to be able to selectively sensitize malignant tissues, and allow lower doses of radiation or treatment to achieve the same curative effect and damage healthy tissues. Less harmful medicine. Similarly, it is also desirable to obtain drugs that can prevent the occurrence or recurrence of cancer.

Many chemotherapeutic drugs for intravenous injection have been developed today. However, due to the ease of administration, better patient compliance, cost reduction and improvement of the quality of life of patients, the use of oral anticancer agent therapy is of great significance. For example, patients will be able to receive oral treatment as outpatients. Therefore, oral drugs for cancer treatment have a promising future and will play a more important role than in the past.

Arsenic compounds have been used as agents for the treatment of various diseases including cancer. Inorganic arsenic compounds are quite toxic. With the rapid development of medicine in the 20th century, the use of medicinal arsenic quickly faded. When daily intravenous injection of arsenic trioxide (As ₂ O ₃ ) alone resulted in a complete response in most newly diagnosed and relapsed acute promyelocytic leukemia patients, interest in arsenic compounds reappeared. The disadvantage of arsenic trioxide is that it is administered intravenously for 1-4 hours every day for up to 6 weeks.

When arsenic trioxide is taken orally, it will combine with chloride ions in the stomach to produce arsenic chloride (AsCl ₃ ). Arsenic chloride is toxic and exhibits serious adverse side effects. Due to the inherent toxicity of arsenic compounds when taken orally, the therapeutic interest for arsenic compounds is still low. However, it has been realized that oral formulations are easy to administer to patients and improve patient compliance.

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

The inventor of this case has developed an enteric film-coated solid pharmaceutical composition containing sodium meta-arsenite (O=As-O ^- Na ⁺ ) or potassium meta-arsenite (O=As-O ^- K ⁺ ), which is suitable for It is administered orally, and it passes through the stomach and begins to dissolve in the small intestine (the acidity is between pH 6.5-7.5).

In the first aspect, the present invention provides a pharmaceutical composition suitable for oral administration, which comprises: (a) a solid core comprising sodium meta-arsenite or potassium meta-arsenite, and one or more pharmaceutically acceptable Accepted excipients, wherein the one or more pharmaceutically acceptable excipients are selected to The oxidation reaction of meta-arsenite to meta-arsenate can be minimized; and (b) an enteric film coating containing an enteric polymer; wherein the weight percentage of the enteric film coating is related to the pharmaceutical composition The total weight is from about 6% w/w to about 20% w/w, and the thickness of the film coating is from about 6.5% to about 15% of the thickness of the pharmaceutical composition.

For example, in the above aspect, the one or more pharmaceutically acceptable excipients can be selected from fillers or diluents, disintegrants, glidants, lubricants, and binders. In some specific examples, the solid core may include two or more of these excipients, three or more of these excipients, four or more of these excipients, or all of these excipients. Therefore, in some embodiments, the solid core includes 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, which comprises: (a) a solid core comprising sodium metaarsenite or potassium metaarsenite, and the following pharmaceutically acceptable The excipients: (i) fillers or diluents, which range from about 5 to 95% w/w, (ii) disintegrants, which range from about 10 to 90% w/w, (iii) Glidants, which range from about 0.1 to 5% w/w, (iv) lubricants, which range from about 0.1 to 5% w/w, and (v) any binders, which range from 0 to About 30% w/w; and (b) an enteric film coating containing an enteric polymer; wherein the pharmaceutically acceptable excipients are selected so that the oxidation of meta-arsenite to meta-arsenate is a reaction Can be minimized, Wherein, the weight percentage of the enteric film coating is about 6% w/w to about 20% w/w relative to the total weight of the medical composition, and wherein the thickness of the film coating is about 6.5 w/w of the thickness of the medical composition % To about 15%.

Those skilled in this area should understand that some excipients have multiple functions. When the excipient contained in the pharmaceutical composition of the present invention has multiple functions, it should be considered that the pharmaceutical composition includes excipients with those functions. If the excipient serves as both a binder and a disintegrant, it should be understood The medical composition includes a binder and a disintegrant.

Preferably, the pharmaceutically acceptable excipient in the solid core has low water content or low water activity so as to minimize the possibility of oxidation of metaarsenite to metaarsenate. Therefore, preferably, the pharmaceutical composition of the present invention does not contain excipients with high water content or high water activity.

The pharmaceutical composition can be in the form of enteric film-coated tablets or enteric film-coated capsules. In some specific examples, the pharmaceutical composition is an enteric film-coated tablet. In some specific examples, the pharmaceutical composition is an enteric film-coated capsule.

In the third aspect, the present invention provides a method for manufacturing the pharmaceutical composition of the first aspect. The method includes the following steps: (a) an active pharmaceutical composition selected from sodium meta-arsenite and potassium meta-arsenite ( API) is blended with one or more pharmaceutically acceptable excipients to form a powder blend, wherein the one or more pharmaceutically acceptable excipients are selected so that the oxidation of metaarsenite becomes partial The reaction of arsenate can be minimized; (b) the powder blend formed in step (a) is compressed to form a solid core; and (c) an enteric film coating containing enteric polymers Coating the solid core; wherein the weight percentage of the enteric film coating is about 6% w/w to about 20% w/w relative to the total weight of the pharmaceutical composition, and wherein the thickness of the film coating is the The thickness of the pharmaceutical composition ranges from about 6.5% to about 15%.

In the fourth aspect, the present invention provides a method for manufacturing the pharmaceutical composition of the second aspect. The method includes the following steps: (a) an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite ) Is blended with the following pharmaceutically acceptable excipients to form a powder blend: (i) filler or diluent, ranging from about 5 to 95% w/w, (ii) disintegrant, which The range is from about 10 to 90% w/w, (iii) glidant, the range is from about 0.1 to 5% w/w, (iv) lubricant, the range is from about 0.1 to 5% w/w , And (v) any binder, the range is from 0 to about 30% w/w; (b) the powder blend formed in step (a) is compressed to form a solid core; and (c) The solid core is coated with an enteric film coating containing an enteric polymer; wherein the pharmaceutically acceptable excipient is selected so that the oxidation reaction of metaarsenite to metaarsenate can be reduced to The smallest, wherein the weight percentage of the enteric film coating is from about 6% w/w to about 20% w/w relative to the total weight of the pharmaceutical composition, and wherein the thickness of the film coating is the thickness of the pharmaceutical composition From about 6.5% to about 15%.

In the fifth aspect, the present invention provides the pharmaceutical composition of the first or second aspect for the treatment of a disease or disorder, wherein the disease or disorder is selected from solid malignant tumors, bone metastases, metastatic tumor diseases, primary Or metastatic lung tumors, urogenital cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disease, immune disease, diabetic retinopathy, diabetic vascular disease, diabetic neuralgia , Symptoms related to insulitis and ulcerative colitis.

In a sixth aspect, the present invention provides a method for treating diseases and disorders in an individual, which comprises orally administering the pharmaceutical composition of the first or second aspect to the individual, wherein the disease or disorder is selected from solid malignancies , Bone metastasis, metastatic tumor disease, primary or metastatic lung tumor, urogenital cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disease, immune disease, diabetes Retinopathy, diabetic vascular disease, diabetic neuralgia, symptoms related to insulitis, and ulcerative colitis.

In a seventh aspect, the present invention provides a use of the pharmaceutical composition of the first or second aspect in the manufacture of oral medicines for the treatment of diseases or disorders, wherein the diseases or disorders are selected from solid malignancies, bone metastases, metastases Neoplastic diseases, primary or metastatic lung tumors, genitourinary system cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disease, immune disease, diabetic retinopathy, diabetes Vascular disease, diabetic neuralgia, symptoms related to insulitis, and ulcerative colitis.

Detailed description of specific examples of the present invention

The preferred specific examples of the present invention are only described below by way of examples.

1. Definition

Unless otherwise defined herein, it should be understood that the following terms have the following general meanings. Unless otherwise specified, 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.

The term "composition" encompasses compositions and formulations containing active pharmaceutical ingredients ("API") and excipients or carriers, as well as compositions and formulations containing encapsulated substances as carriers to provide a capsule, wherein the active pharmaceutical ingredient The components (with or without other carriers) are surrounded by encapsulated carriers. In the pharmaceutical composition, the excipient or carrier is "pharmaceutically acceptable" meaning that it is not biologically or otherwise undesirable, and also That is, the substance can be incorporated into a pharmaceutical composition administered to a patient without causing any unwanted biological effects or interactions with any other components in the composition containing it in a harmful manner.

"Pharmaceutically acceptable", as described in "pharmaceutically acceptable salt" or "pharmaceutically acceptable excipient or carrier", as used herein means a substance that is not physiologically or otherwise undesirable That is, the substance can be incorporated into a pharmaceutical composition administered to a patient without producing any undesired biological effects or interacting with any other components contained in the composition in a harmful manner.

The term "effective amount" or "therapeutically effective amount" refers to the amount of an active pharmaceutical ingredient, which is sufficient to produce the desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic reaction). When the method of the present invention is used, it is consistent with a reasonable benefit/risk ratio. For example, this amount can effectively delay growth, delay metastasis, inhibit angiogenesis and/or telomere, and/or cause cancer to shrink. The specific effective amount or therapeutically effective amount will depend on the specific disease, age, weight, general health, physical condition, gender and diet of the individual to be treated, the duration of treatment, the nature of the co-treatment (if any), and the specific The severity of the disease varies.

As used herein, the word "about" means a slight variation of the specified value, preferably within 10% of the specified value. However, the word "about" can mean a higher tolerable variation based on, for example, the experimental technique used. The variation of the specific value should be understood by those skilled in this aspect and is included in the context of the present invention. Furthermore, in order to provide a more concise description, some quantitative expressions in this article are not standardized by the word "about". It is understood that regardless of whether the word "about" is used explicitly or not, each quantity given in this article refers to the actual value given, and it also means such a given value that can be reasonably inferred based on the general skills in this field Approximate values include equivalent and approximate values due to the experimental and/or measurement conditions of these given values.

Unless otherwise indicated, in this text, all amounts are expressed in weight percent (% w/w).

Of course, any substance used in the manufacture of the pharmaceutical composition of the present invention should be medically pure and substantially non-toxic in its usage amount.

2. The chemical properties of meta-arsenite

Sodium meta-arsenite and potassium meta-arsenite can be synthesized from arsenic trioxide (As ₂ O ₃ ). For example, sodium meta-arsenite can be formed by reacting arsenic trioxide (As ₂ O ₃ ) with aqueous sodium hydroxide to form sodium meta-arsenite (the upper left of the following process 1). The solution is cooled, the sodium metaarsenite is filtered out, and the water is evaporated. The formed sodium metaarsenite was then washed with methanol to remove water, filtered in vacuum, and then dried. Potassium metaarsenite can be prepared by using aqueous potassium hydroxide instead of aqueous sodium hydroxide in a manner similar to sodium metaarsenite.

However, the main problem of arsenite (O=As-O ^- salt) is its morphological chemistry and its ability to transform into many different forms in solution, such as when it contains sodium meta-arsenite (O=As-O ^- Na ⁺⁾ or potassium meta arsenite ^{(O = As-O - K} +) of the oral dosage form when dissolved in the stomach. For example, sodium metaarsenite (O=As-O ^- Na ⁺ ) is easily soluble in strong acids, strong bases, and neutral conditions. The type of existence depends on the pH of the solution and the oxidation tendency of sodium meta-arsenite (the following process 1). Potassium meta-arsenite behaves similarly to sodium meta-arsenite. Generally, neutral to alkaline conditions tend to favor the formation (or retention) of As(III) (arsenite) whereas acidic conditions (especially in the presence of chloride ions, such as in the stomach) tend to favor the formation of As (V) (Arsenate).

In addition, during storage, when chlorine, metal ions or moisture (such as in the dissolution medium or in excipients; excipients can catalyze oxidation, such as excipients containing metal ions, especially iron), or when the presence of atmospheric oxygen, arsenite (O = as-O ^-) partial oxidized to arsenate. At low pH, the oxidation of meta-arsenite can occur very quickly. Both sodium meta-arsenite (O=As-O ^- Na ⁺ ) and potassium meta-arsenite (O=AO ^- K ⁺ ) are hygroscopic.

In the solution, the main degradation product of sodium meta-arsenite is the pentavalent sodium meta-arsenite (AsO ₄ ³ -or As(V)) species formed by oxidation reaction. It is assumed that it can proceed as shown in Box 1 below. However, in theory, the oxidation reaction (change in valence) can occur without absorbing oxygen (for example, by interaction with excipients or partial Reaction of sodium arsenite or metal ions in the composition).

Other complications caused by the dissolution of sodium meta-arsenite (O=As-O ^- Na ⁺ ) or potassium meta-arsenite (O=As-O ^- K ⁺ ) in the stomach are the formation of chlorine from chloride ions in the stomach Arsenic (III) (AsCl ₃ ). When chloride ions are present, the oxidation reaction of meta-arsenite can occur faster. Arsenic (III) chloride is toxic to the human body and causes serious side effects.

The inventor of this case has developed an enteric film-coated solid pharmaceutical composition containing sodium meta-arsenite or potassium meta-arsenite, which is suitable for oral administration, and it passes through the stomach and begins to dissolve in the small intestine (its acidity is related to At pH 6.5-7.5). The risk of oxidation of the meta-arsenite form to the meta-arsenate form (in the stomach or during storage) and the risk of the formation of toxic arsenic (III) chloride from chloride ions in the stomach can be achieved by using appropriate excipients Forms and carriers, and appropriate enteric film coating of appropriate thickness to minimize. In the small intestine, the dissolution of the enteric film-coated solid medical composition can occur quickly or over an extended period of time (such as 0.5, 0.75, 1, 2, 3, 4, 5 or 6 hours, preferably within 2 hours) .

Preferred specific examples of the pharmaceutical composition of the present invention are described below. The pharmaceutical composition of the present invention can be produced by the following effective methods.

3. The pharmaceutical composition of the present invention

In the first aspect, the present invention provides a pharmaceutical composition suitable for oral administration, which comprises: (a) a solid core comprising sodium metaarsenite or potassium metaarsenite, and one or more pharmaceutically acceptable Accepted excipients, wherein the one or more pharmaceutically acceptable excipients are selected so that the oxidation reaction of meta-arsenite to meta-arsenate can be minimized; and (b) enteric film Coat, which contains an enteric polymer; Wherein, the weight percentage of the enteric film coating is about 6% w/w to about 20% w/w relative to the total weight of the medical composition, and the thickness of the film coating is about the thickness of the medical composition. 6.5% to about 15%.

For example, in the above aspect, the one or more pharmaceutically acceptable excipients can be selected from fillers or diluents, disintegrants, glidants, lubricants, and binders. In some embodiments, the solid core may include two or more of these excipients, three or more of these excipients, four or more of these excipients, or all of these excipients. Therefore, in some embodiments, the solid core includes fillers or diluents, disintegrants, glidants, lubricants, and binders.

In the second aspect, the present invention provides a pharmaceutical composition suitable for oral administration, which comprises: (a) a solid core comprising sodium meta-arsenite or potassium meta-arsenite, and the following pharmaceutically acceptable Excipients: (i) fillers or diluents, ranging from about 5 to 95% w/w, (ii) disintegrants, ranging from about 10 to 90% w/w, (iii) auxiliary Flow agent, the range is from about 0.1 to 5% w/w, (iv) lubricant, the range is from about 0.1 to 5% w/w, and (v) any binder, the range is from 0 to about 30% w/w; and (b) an enteric film coating, which contains an enteric polymer; wherein the pharmaceutically acceptable excipients are selected so that the meta-arsenite is oxidized to meta-arsenate The reaction can be minimized, wherein the weight percentage of the enteric film coating is from about 6% w/w to about 20% w/w relative to the total weight of the pharmaceutical composition, and wherein the thickness of the film coating is The thickness of the medical composition ranges from about 6.5% to about 15%.

The form of the pharmaceutical composition can be enteric film-coated tablets or enteric film-coated capsules. In some specific examples, the pharmaceutical composition is an enteric film-coated tablet. In some specific examples, the pharmaceutical composition is an enteric film-coated capsule.

3.1 Active pharmaceutical ingredients (API) (sodium or potassium meta-arsenite)

In the pharmaceutical composition of the present invention, the active pharmaceutical component (API) is sodium meta-arsenite or potassium meta-arsenite.

Sodium meta-arsenite and potassium meta-arsenite are commercially available in high purity (>98% As(III) and a minimum amount of As(V)). Sodium meta-arsenite and potassium meta-arsenite are hygroscopic.

As inorganic compounds, sodium meta-arsenite and potassium meta-arsenite each have a relatively high particle (true) density (for example, sodium meta-arsenite is about 2.1 to 2.3 g/cm ³ , and potassium meta-arsenite is about 8.76 g/cm ³ ), compared with typical tablet excipients (typical tablet excipients are usually organic substances with a density of approximately 1.2 to 1.6 g/cm ³ ).

When there is a difference between the particle size of the API and the particle size of the excipients, the possibility of the API in the composition disintegrating is high. Those skilled in this aspect should understand that the use of APIs with a better particle size can advantageously guide the improvement of powder mixing and blending uniformity, minimize or eliminate powder disintegration during compression, and achieve satisfactory results in the composition. Satisfactory content uniformity.

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

In some specific examples, the API is sodium metaarsenite.

In some specific examples, 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 to 5.0% w/w of the solid core, preferably about 0.5 to 3.0% w/w of the solid core, It is more preferably about 1.0 to 2.5% w/w of the solid core, and even more preferably about 1.5 to 2.0% w/w of the solid core, and most It is preferably about 1.6 to 1.8% w/w of the solid core, such as about 1.65% w/w of the solid core, 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, about 1.74% w/w, or about 1.75% w/w.

In some specific cases, the particle size of API and the particle size of pharmaceutically acceptable excipients are similar. Advantageously, the use of APIs and excipients of similar particle size can lead to improve powder mixing and blending uniformity, minimize or eliminate powder disintegration during compression, and achieve satisfactory content uniformity in the composition Sex.

In some specific cases, the API is micronized. Those skilled in this aspect should understand that when the API is present in a low amount, reducing the particle size of the API by micronization can improve the uniformity of blending and content uniformity in dosage forms (such as tablets).

In some specific cases, the API is not micronized. Those skilled in this area should understand that micronization of hygroscopic APIs (such as sodium meta-arsenite and potassium meta-arsenite) will increase the risk of decomposition due to higher surface area and reactivity.

3.2 Pharmaceutically acceptable excipients

In one aspect, in addition to sodium meta-arsenite or potassium meta-arsenite, the solid core of the pharmaceutical composition of the present invention contains one or more pharmaceutically acceptable excipients, which are selected so that the meta-arsenite oxidizes The reaction to meta-arsenate can be minimized.

In some embodiments, the pharmaceutically acceptable excipient is selected so that less than about 10% w/w, preferably less than about 5% w/w, more preferably less than about 2% w/w w, even more preferably less than about 1% w/w, and most preferably less than about 0.5% w/w of sodium meta-arsenite or potassium meta-arsenite, stored 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 after oxidation to sodium meta-arsenate or potassium meta-arsenate .

On the other hand, in addition to sodium meta-arsenite or potassium meta-arsenite, the solid core of the pharmaceutical composition of the present invention contains the following pharmaceutically acceptable excipients: (i) filler or diluent, (ii) disintegrant, (iii) glidant, (iv) lubricant, and (v) optional binder.

Those skilled in this area should understand that some excipients have multiple functions. When the excipients contained in the pharmaceutical composition of the present invention have multiple functions, the pharmaceutical composition is considered to contain excipients with these functions. If the excipient functions as both a binder and a disintegrant, it should Understand that the pharmaceutical composition includes binders and disintegrants.

Generally, one or more pharmaceutically acceptable excipients in the solid core are compatible with sodium or potassium meta-arsenite. Preferably, the pharmaceutically acceptable excipients in the solid core have low water content or low water activity so that the possibility of oxidation of metaarsenite to metaarsenate is minimized. Therefore, preferably, the pharmaceutical composition of the present invention does not contain excipients with high water content or high water activity (for example, excipients that can catalyze oxidation, such as excipients containing metal ions, especially iron). However, those skilled in the art should understand that the utility of the pharmaceutical composition of the present invention is limited because some available water must be used to satisfy the suppression.

In some specific examples, the particle size of the API and the particle size of the pharmaceutically acceptable excipient are similar. Advantageously, the use of APIs and excipients of similar particle size can lead to improved powder mixing and blending uniformity, minimize or eliminate disintegration in the powder during compression, and achieve satisfactory results in the solid core The content uniformity.

In some specific cases, when possible, try to choose a higher-density main excipient to match the density of sodium or potassium meta-arsenite (the estimated true density of sodium meta-arsenite is about 2.1 to 2.3 g/cm ³ , and the estimated true density of potassium metaarsenite is about 8.76 g/cm ³ ); typical tablet excipients are organic substances with a density of about 1.2 to 1.6 g/cm ³ .

The filler or diluent can be, for example, selected from the group consisting of binary anhydrous calcium hydrogen phosphate, partially pregelatinized starch, silicified microcrystalline cellulose, microcrystalline cellulose, calcium sulfate dihydrate, lactose, calcium hydrogen phosphate, calcium carbonate , Sodium carbonate, calcium phosphate, sodium phosphate, or mixtures thereof. In some specific examples, the filler or diluent is dibasic anhydrous calcium hydrogen phosphate, partially pregelatinized starch, or a mixture thereof. In some specific examples, the filler or diluent is dibasic anhydrous calcium hydrogen phosphate. In some embodiments, the filler or diluent is partially pregelatinized starch. In some embodiments, the diluent may be a compressible diluent, such as silicified microcrystalline cellulose, microcrystalline cellulose, or partially pregelatinized starch.

The amount of filler or diluent present in the solid core of the medical composition is about 5 to 95% w/w of the solid core. In some embodiments, the amount of the filler or diluent in the solid core of the pharmaceutical composition is about 10 to 90% w/w of the solid core, such as about 10% w/w of the solid core. , About 15% w/w of solid core, about 20% w/w of solid core, about 25% w/w of solid core, about 30% w/w of solid core, about 30% w/w of solid core 35% w/w, about 40% w/w of solid core, about 45% w/w of solid core, about 50% w/w of solid core, and about 55% w/w of solid core, About 60% w/w of solid core, about 65% w/w of solid core, about 70% w/w of solid core, about 75% w/w of solid core, about 80% w/w of solid core % w/w, about 85% w/w of the solid core, or about 90% w/w of the solid core.

The disintegrant may, for example, be selected from L-hydroxypropyl cellulose, partially pregelatinized starch, cross-linked polyvinylpyrrolidone, potato starch, corn starch, sodium starch glycolate, and alginic acid. Sodium starch glycolate and cross-linked polyvinylpyrrolidone are super disintegrants. In some embodiments, the disintegrant is L-hydroxypropyl cellulose, partially pregelatinized starch, sodium starch glycolate, or a mixture of two or more of them. In some specific examples, the disintegrant is L-hydroxypropyl cellulose. In some specific examples, the disintegrant is partially pregelatinized starch. In some specific examples, the disintegrant is sodium starch glycolate.

The amount of disintegrant present in the solid core of the pharmaceutical composition is about 10 to 90% w/w of the solid core, such as about 10 to 50% w/w of the solid core. In some specific examples, the amount of disintegrant present in the solid core of the pharmaceutical composition is about 15 to 85% w/w of the solid core, such as about 15% w/w of the solid core. About 20% w/w of core, about 25% w/w of solid core, about 30% w/w of solid core, about 35% w/w of solid core, and about 40% of solid core w/w, about 45% w/w of solid core, about 50% w/w of solid core, about 55% w/w of solid core, about 60% w/w of solid core, solid core About 65% w/w of the core, about 70% w/w of the solid core, about 75% w/w of the solid core, about 80% w/w of the solid core, or about 85% of the solid core w/w.

The glidant may, for example, be selected from colloidal silica and talc. In some specific examples, the glidant is colloidal silica. In some specific examples, the glidant is talc.

The amount of glidant present in the solid core of the pharmaceutical composition is about 0.1 to 5% w/w of the solid core. In some specific examples, the amount of glidant present in the solid core of the pharmaceutical composition is about 0.3 to 4% w/w of the solid core, such as about 0.3% w/w of the solid core. About 0.4% w/w for cores, about 0.5% w/w for solid cores, about 0.6% w/w for solid cores, about 0.7% w/w for solid cores, and about 0.8% for solid cores w/w, about 0.9% w/w of solid core, about 1.0% w/w of solid core, about 1.1% w/w of solid core, about 1.2% w/w of solid core, solid core The core is about 1.3% w/w, the solid core is about 1.4% w/w, the solid core is about 1.5% w/w, the solid core is about 1.6% w/w, and the solid core is about 1.7% w /w, about 1.8% w/w of solid core, about 1.9% w/w of solid core, about 2.0% w/w of solid core, about 2.1% w/w of solid core, solid core About 2.2% w/w of solid core, about 2.3% w/w of solid core, about 2.4% w/w of solid core, about 2.5% w/w of solid core, and about 2.6% w/ of solid core w, about 2.7% w/w of solid core, about 2.8% w/w of solid core, about 2.9% w/w of solid core, about 3.0% w/w of solid core, and about solid core About 3.1% w/w, about 3.2% w/w for solid cores, about 3.3% w/w for solid cores, about 3.4% w/w for solid cores, and about 3.5% w/w for solid cores , About 3.6% w/w of solid core, about 3.6% w/w of solid core 3.7% w/w, solid core about 3.8% w/w, solid core about 3.9% w/w, or solid core about 4.0% w/w.

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

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

If present, the binder can, for example, be selected from silicified microcrystalline cellulose, microcrystalline cellulose, partially pregelatinized starch, L-hydroxypropyl cellulose (low-substituted hydroxypropyl cellulose), hydroxypropyl fiber Vegetarian, povidone (polyvinylpyrrolidone), pregelatinized corn starch, hydroxypropyl methylcellulose, starch, acacia, corn starch, and gelatin. In some embodiments, the binder is L-hydroxypropyl cellulose (low-substituted hydroxypropyl cellulose). In some embodiments, the binder is a mixture of L-hydroxypropyl cellulose (low-substituted hydroxypropyl cellulose) and hydroxypropyl cellulose. In some specific examples, the binder is partially pregelatinized starch.

The amount of the binder present in the solid core of the medical composition is about 0 to 30% w/w of the solid core. In some embodiments, the amount of binder present in the solid core of the pharmaceutical composition is about 1 to 30% w/w of the solid core, such as about 5 to 25% w/w of the solid core. w. For example, the amount of binder present in the solid core of the pharmaceutical composition is about 5% w/w of the solid core, about 10% w/w of the solid core, and about 15% w/w of the solid core. The solid core is about 20% w/w, the solid core is about 25% w/w, and the solid core is about 30% w/w.

The pharmaceutical composition of the present invention may optionally contain an antioxidant in the solid core. Antioxidants function as reducing agents by: (a) lowering the redox potential, (b) scavenging oxygen, or (c) terminating free radical reactions (acting as a free radical inhibitor). Mechanisms (a) and (b) are most related to the degradation of sodium or potassium meta-arsenite into sodium or potassium meta-arsenite. Advantageously, the antioxidant is used to reduce or prevent the oxidation of As(III) in the composition to As(V).

Examples of antioxidants used in solid cores 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 amount of antioxidant present in the solid core is about 0.01 to 0.2% w/w of the solid core, such as 0.01% w/w, 0.02% w/w, 0.03% w/w, 0.04% w/w , 0.05% w/w, 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.

It should be understood that those skilled in this area should understand that the amount of API (sodium meta-arsenite or potassium meta-arsenite), excipients and other components in the solid core should be adjusted to the solid core Of 100%.

Advantageously, the solid core of the pharmaceutical composition of the present invention has good blending uniformity and content uniformity due to the use of the above-mentioned appropriate excipients.

In some specific examples, the solid core of the pharmaceutical composition of the present invention does not contain any one or more of the following: silicified microcrystalline cellulose, microcrystalline cellulose, calcium sulfate dihydrate, povidone (polyvinylpyrrolidone), Cross-linked polyvinylpyrrolidone, stearic acid, talc, and sodium metabisulfite.

3.3 Enteric film coating

The pharmaceutical composition of the present invention includes an enteric film coating containing an enteric polymer. The enteric film coating can be applied by an appropriate coating technique known in the art. The enteric film coating material can be dispersed or dissolved in water or a suitable organic solvent.

As the enteric film coating polymer, one or more of the following can be used separately or in combination, for example: acrylic acid copolymer solution or dispersion and its ester or methacrylic acid or its ester, polysorbate, acetic acid Cellulose phthalate polymer, hydroxypropyl methyl cellulose phthalate polymer, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, trimellit acetate Acid cellulose, carboxymethyl ethyl cellulose, shellac, or other suitable enteric film-coated polymers.

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

Enteric film-coated polymer products are available from Rohm GmbH & Co., Darmstadt, Germany under the trade name EUDRAGIT®, 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 poly(methacrylic acid-co-ethyl acrylate) (1:1). EUDRAGIT S100 is a methacrylic acid-methyl methacrylate copolymer (1:2). EUDRAGIT L30D-55 is an aqueous dispersion of a pH-dependent polymer, soluble in pH 5.5 or above, for targeted delivery in the duodenum. The methacrylic acid copolymer EUDRAGIT L30D-55 is a copolymer of methacrylic acid and ethyl acrylate at a ratio of 1:1 and has the chemical formula (C ₅ H ₂ O ₂ ˙C ₄ H ₆ O ₂ ) _x .

Acryl-EZE® from Colorcon is an aqueous acrylic enteric system that can be dispersed in water and used to apply enteric film coatings to solid dosage forms such as lozenges, granules and granules. Examples of useful Acryl-EZE® products include Acryl-EZE II white (493Z180022) and Acryl-EZE Green (93O11863).

The enteric film coating may further contain a pharmaceutically acceptable plasticizer to obtain desired physical characteristics, such as the flexibility and hardness of the enteric film coating. These plasticizers are, for example, but not limited to, triacetin, citrate, phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate or Other plasticizers. The anti-sticking agent is, for example, magnesium stearate, titanium dioxide, talc, and other additives may also be included in the enteric film coating.

In some embodiments, the enteric film coating provides a solid core weight increase of about 7 to 17% w/w, such as a solid core weight increase of about 8 to 14% w/w. In some embodiments, the enteric film coating provides about 8% w/w weight gain, about 8.5% w/w weight gain, about 9% w/w weight gain, about 9.5% w/w, about 10% w/w /w weight increase, about 10.5% w/w weight increase, about 11% w/w weight increase, about 11.5% w/w weight increase, about 12% w/w weight increase, about 12.5% w/w weight increase, About 13% w/w weight gain, about 13.5% w/w weight gain, or about 14% w/w weight gain. In some embodiments, the enteric film coating provides a solid core weight increase of about 12% w/w.

In some embodiments, the solid core can be sub-coated with a polymer known in the art for proper sub-coating before being coated with an enteric film coating.

3.4 Types of the pharmaceutical composition of the present invention

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

In some specific examples, the pharmaceutical composition of the present invention is an enteric film-coated tablet with a solid core diameter of about 5 to 8 mm. This diameter is the widest dimension of the solid core. In some embodiments, the diameter of the solid core is about 5.5 to 7.5 mm. In some embodiments, the diameter of the solid core is 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 film-coated tablet with a solid core diameter of 6.5 mm. More preferably, the pharmaceutical composition of the present invention is an enteric film-coated tablet with a solid core diameter of 6.5 mm, and it contains sodium meta-arsenite.

In some embodiments, the thickness of the solid core of the enteric film-coated tablet can be from about 2 mm to 6 mm, such as from about 2 mm to 5 mm. The thickness of the solid core of the enteric film-coated tablet is the depth of the solid core, that is, the height of the solid core measured when the solid core is placed on a flat surface. In some embodiments, the thickness of the solid core of the enteric film-coated tablet is about 3 to 4.5 mm. In some embodiments, the thickness of the solid core of the enteric film-coated tablet is about 3.1 to 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 3.7mm, about 3.8mm, about 3.9mm, about 4.0mm, about 4.1mm, or about 4.2mm. Preferably, the thickness of the solid core of the enteric film-coated tablet 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 specific examples, the pharmaceutical composition of the present invention is an enteric film-coated capsule, the length of the solid core is from about 8.0 to 16 mm. In some embodiments, the length of the solid core is about 8.5 to 15 mm. In some embodiments, the length of the solid core is about 8.5 to 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 11.0 mm, about 11.5 mm, about 12.0 mm, about 12.5mm, about 13.0mm, about 13.5mm, about 14mm, or about 14.5mm. Preferably, the pharmaceutical composition of the present invention is an enteric film-coated capsule with a solid core length of about 14.3 mm. More preferably, the pharmaceutical composition of the present invention is an enteric film-coated capsule with a solid core of about 14.3 mm in length, and it contains sodium metaarsenite.

In some embodiments, the thickness of the solid core of the enteric film-coated capsule may be from about 3 mm to 8 mm, such as from about 4.0 mm to 7.0 mm. The thickness of the solid core of the enteric film-coated capsule is the depth of the solid core, that is, the height of the solid core measured when the solid core rests on a flat surface. In some embodiments, the thickness of the solid core is about 4.5 to 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 5.0 mm, about 5.1 mm, about 5.2 mm, 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 solid core of the enteric film-coated capsule is about 5.31 mm.

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

In some embodiments, the friability of the solid core 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, it is less than about 0.3%. In some embodiments, the friability of the solid core is less than about 0.25%. In some specific cases, the solid The friability of the body core is less than about 0.2%. In some embodiments, the friability of the solid core 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 specific examples, the mass of the solid core is from about 50 mg to 250 mg. In some specific examples, the mass of the solid core is about 80 mg to 220 mg. In some specific examples, the mass of the solid core is from about 100 mg to 200 mg. In some embodiments, the mass of the solid core is from about 120 mg to 180 mg. In some embodiments, the mass of the solid core is from about 140 mg to 160 mg, such as about 140 mg, about 145 mg, about 150 mg, about 155 mg or about 160 mg. Preferably, the mass of the solid core is 150 mg.

In some specific examples, the pharmaceutical composition of the present invention comprises a solid core selected from the group consisting of: ˙Solid core comprising sodium metaarsenite, binary anhydrous calcium hydrogen phosphate, L-hydroxypropyl cellulose, hydroxypropyl cellulose Base cellulose, colloidal silica, and sodium stearyl fumarate; ˙Solid core, which contains sodium metaarsenite, binary anhydrous calcium hydrogen phosphate powder, part of pregelatinized starch, binary anhydrous Calcium hydrogen phosphate, sodium starch glycolate, colloidal silica, and sodium stearyl fumarate; ˙Solid core, which contains sodium meta arsenite, binary anhydrous calcium hydrogen phosphate powder, binary anhydrous phosphoric acid Calcium hydrogen, L-hydroxypropyl cellulose, sodium starch glycolate, colloidal silica, and sodium stearyl fumarate; ˙solid core, which contains sodium metaarsenite, binary anhydrous hydrogen phosphate Calcium, partially pregelatinized starch, sodium starch glycolate, colloidal silica, and sodium stearyl fumarate; and ˙solid core, which contains sodium metaarsenite, binary anhydrous calcium hydrogen phosphate, Silicified microcrystalline cellulose, sodium starch glycolate, colloidal silica, and sodium stearyl fumarate.

In some specific examples, the pharmaceutical composition of the present invention is an enteric film-coated tablet containing a solid core of 1.67% w/w sodium metaarsenite, and the diameter of the solid core is about 6.5 mm, and the mass of the solid core It is 150mg, and enteric-coated film, the added amount is about 12% w/w of the solid core.

In some specific examples, the pharmaceutical composition of the present invention is an enteric film-coated tablet, which contains a solid core of 1.67% w/w sodium metaarsenite, and the diameter of the solid core is about 6.5 mm. The core mass is 150mg, and the film coating thickness is about 0.2mm enteric coating.

In some specific examples, after the pharmaceutical composition of the present invention is administered, the pharmaceutical composition has the following dissolution characteristics: not less than 75% within 45 minutes, preferably not less than 75% within 30 minutes.

In some specific cases, in the small intestine, the dissolution of the pharmaceutical composition of the present invention and the release of API occur rapidly or over an extended period of time (such as 0.5, 0.75, 1, 2, 3, 4, 5 or 6 hours, preferably Within 2 hours).

In some embodiments, when the enteric film coating is dissolved, the solid core takes less than about 10 minutes, preferably less than about 8 minutes, more preferably less than about 6 minutes, and even more preferably less than about 5 minutes. Minutes, and most preferably disintegrate in less than about 4 minutes.

The pharmaceutical composition of the present invention is preferably presented in a unit dose form. The unit dose form may be a packaged preparation, the package containing separate quantities of pharmaceutical composition, such as a packaged tablet or capsule. Moreover, the unit dosage form may be a tablet or capsule itself, or it may be an appropriate number of any of these in a package form. The packaged type may, for example, include metal or plastic foil, such as a blister package, such as an aluminum-aluminum blister package, which is impermeable or impermeable to oxygen. The packaging format can be accompanied by instructions for administration.

In some specific cases, the pharmaceutical composition of the present invention can be stored in the surrounding or room temperature for at least 3 months, preferably at least 6 months, more preferably at least 1 year, and most preferably 18-24 months. In some embodiments, the pharmaceutical composition of the present invention can be refrigerated (for example, at about 2-8°C).

3.5 Dosage

The appropriate dosage of the sodium or potassium meta-arsenite can be easily determined by those skilled in this aspect.

The appropriate dosage level of sodium or potassium meta-arsenite administered to an individual is generally about 0.01-0.8 mg/kg individual body weight/day, such as about 0.05-0.7 mg/kg individual body weight/day, about 0.1-0.6 mg /Per kg Body weight/day, or about 0.2-0.5 mg/kg individual body weight/day, which can be administered in a single dose or multiple doses per day.

For example, the appropriate dosage of sodium or potassium meta-arsenite administered to a patient (such as a cancer patient) is about 2.0 to 30 mg/day/patient, such as about 2.5 to 20.0 mg/day/patient or about 2.5 to 17.5 mg/patient Days/patients. Preferably, the dosage level of sodium or potassium meta-arsenite is about 5.0 to 12.5 mg/day/patient, more preferably about 10.0 to 12.5 mg/day/patient, such as 5.0 mg/day/patient, 5.5 mg /Day/patient, 6.0mg/day/patient, 6.5mg/day/patient, 7.0mg/day/patient, 7.5mg/day/patient, 8.0mg/day/patient, 8.5mg/day/patient, 9.0mg/ Day/patient, 9.5mg/day/patient, 10.0mg/day/patient, 10.5mg/day/patient, 11.0mg/day/patient, 11.5mg/day/patient, 12.0mg/day/patient, or 12.5mg/ Days/patients.

It should be understood that the specific dosage level and frequency of the dosage of any specific individual can vary and will be based on the individual’s age, weight, general health, gender and diet, the type and time of administration, excretion rate, drug combination, and the severity of the specific situation. Various factors of degree.

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

An exemplary dosing regimen of the lozenge with 2.5mg sodium metaarsenite (SMA) of the present invention is as follows: ￭5.0mg SMA intake: 1x lozenge after breakfast, 1x lozenge after dinner; ￭7.5mg SMA intake: 2x lozenges after breakfast, 1x lozenges after dinner; ￭ 10.0mg SMA intake: 2x lozenges after breakfast, 2x lozenges after dinner.

3.6 Application

The medical composition of the present invention is useful for treating various diseases and diseases in clinical application.

The pharmaceutical composition of the present invention can, for example, be used to treat the following diseases and disorders: ˙Solid malignant tumors, such as colon tumors, stomach tumors, breast tumors, ovarian tumors, prostate tumors, and kidney tumors (belonging to colon tumors, breast tumors, Prostate tumors, and kidney tumors Solid malignant tumors of the family are particularly sensitive to the treatment of sodium metaarsenite); see WO 2003/086424, which is incorporated herein as a reference; ˙solid tumors (such as epithelial tissue; lymphoid tissue; connective tissue; bone; or central Solid tumors of the nervous system, such as neuroblastoma, retinoblastoma, glioblastoma or oligodendroglioma); bone metastases; metastatic tumor diseases (such as cancer of the lymphatic 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 tumors; urogenital cancers such as prostate, bladder, Cancer of the kidney and testis; leukemia (such as acute promyelocytic leukemia, acute myeloid leukemia, and acute lymphoblastic leukemia); see WO 2006/121280, which is incorporated herein as a reference; pain (including cancer pain and Non-cancer related pain, such as visceral pain, postoperative or surgical pain, central pain, chronic pain, neuropathic pain, spinal pain, pain related to infectious diseases, pain related to surgery, headache, burns, angina pectoris , Herpes neuralgia, dental condition, diabetic neuropathy, fibromyalgia, NSAID-impedance symptoms, somatoform disorders, cystitis, muscle damage, dysmenorrhea, osteoarthritis, and stroke); inflammation (including non-cancer related inflammation , Such as those related to asthma, lung disease, autoimmune diseases, arthritis, lupus erythematosus, multiple sclerosis, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, and type I diabetes), autoimmune diseases, And immune diseases (such as tissue rejection or organ rejection); diabetic retinopathy; diabetic angiopathy; diabetic neuralgia; symptoms related to insulitis and ulcerative colitis; see WO 2008/097824, which is incorporated herein as Reference; ˙ Cancer, including cancers related to cancer cells containing chromosomes with long telomeres (such as lung cancer such as non-small cell lung cancer, and prostate cancer); see WO 2009/120697, which is incorporated herein as a reference; ˙ Blood cancer, metastatic cancer, cancer pain, or chronic pain.

3.7 Administration with other drugs

In some specific cases, the pharmaceutical composition of the present invention may be co-administered with one or more other agents.

For example, the pharmaceutical composition of the present invention can be administered together with other therapeutic agents, such as analgesics, anesthetics, antiangina drugs, antifungals, antibiotics, anticancer drugs (e.g., 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, anti- Malaria drugs, anti-microtubule agents (eg, colchicine or vinca alkaloids), anti-migraine drugs, antibacterial agents, antipsychotics, antipyretics, preservatives, anti-signaling agents (eg, protein kinase C inhibitors) Or inhibitors of intracellular calcium mobilization), anti-arthritis drugs, antithrombin agents, anti-tuberculosis drugs, cough suppressants, antiviral drugs, appetite suppressants, heart active drugs, chemical dependence drugs, laxatives, chemotherapeutics, coronary Arterial, brain or peripheral vasodilators, contraceptives, inhibitors, diuretics, expectorants, growth factors, hormones, sleeping pills, immunosuppressants, narcotic antagonists, parasympathomimetic drugs, tranquilizers, stimulants, sympathomimetic Nerve drugs, toxins (eg, cholera toxin), tranquilizers and urinary anti-infectives.

It should be understood that when the pharmaceutical composition of the present invention is administered in combination with one or more other agents, they can be administered simultaneously, sequentially or separately.

4. Manufacturing method of the pharmaceutical composition of the present invention

In a third aspect, the present invention provides a method for manufacturing the pharmaceutical composition of the first aspect, the method comprising the following steps: (a) an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite ) Is blended with one or more pharmaceutically acceptable excipients to form a powder blend, wherein the one or more pharmaceutically acceptable excipients are selected so that the meta-arsenite is oxidized to meta-arsenic The reaction of the acid salt can be minimized; (b) the powder blend formed in step (a) is compressed to form a solid core; And (c) coating the solid core with an enteric film coating containing an enteric polymer; wherein the weight percentage of the enteric film coating is about 6% w/ relative to the total weight of the pharmaceutical composition w to about 20% w/w, and the thickness of the film 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 manufacturing the pharmaceutical composition of the second aspect. The method includes the following steps: (a) an active pharmaceutical ingredient (API) selected from sodium metaarsenite and potassium metaarsenite ) Is blended with the following pharmaceutically acceptable excipients to form a powder blend: (i) filler or diluent, ranging from about 5 to 95% w/w, (ii) disintegrant, which The range is from about 10 to 90% w/w, (iii) glidant, the range is from about 0.1 to 5% w/w, (iv) lubricant, the range is from about 0.1 to 5% w/w , And (v) any binder in the range of 0 to about 30% w/w; (b) the powder blend formed in step (a) will be compressed to form a solid core; and (c) The solid core is coated with an enteric film coating containing an enteric polymer; wherein the pharmaceutically acceptable excipients are selected so that the oxidation reaction of meta-arsenite to meta-arsenate can be reduced To the smallest, wherein the weight percentage of the enteric film coating is from about 6% w/w to about 20% w/w relative to the total weight of the pharmaceutical composition, and wherein the thickness of the film coating is the pharmaceutical composition The thickness is from about 6.5% to about 15%.

In some specific examples of the method of the present invention, the preparation of the solid core does not involve the addition of water or solvent, that is, no water or solvent is added during the preparation of the solid core. Therefore, in some specific cases, The blending step (a) of the third and fourth aspects is performed without water or solvent, and the pressing step (b) of the third and fourth aspects is performed without water or solvent.

The pharmaceutical composition of the present invention can be manufactured with conventional equipment using known techniques in the art.

Generally, the pharmaceutical composition of the present invention can be prepared by blending the components (API and excipients) in the composition to form a blended powder. Since the concentration of API can be extremely low, a two- or three-stage blending process (using "API premix" and "primary mixture") can be used to improve the blending uniformity. The blending time can vary according to the composition. The lubricant can be added at the same time as the other components in the main mixture, or can be added in a separate step later to avoid possible problems due to excessive lubrication (such as reduced tablet hardness or decomposition events). Generally, the blending step is performed without water or solvent, that is, no water or solvent is added during the blending step. After blending, the blended powder is compressed to form a solid core. Generally, no water or solvent is used during the pressing step, that is, no water or solvent is added during the pressing step. The solid core is then coated with an enteric polymer.

Therefore, in some specific examples of the method of the present invention, the blending step (step (a)) includes two steps: the first step includes combining the API (which is preferably screened/sieved) with part of the filler (and a (Any antioxidant) is blended to form an API premix; and the second step includes blending a glidant (which is preferably screened/screened), disintegrant, lubricant, and any binder with the API premix . In some embodiments, no water or solvent is used in the blending step, that is, no water or solvent is added during the blending step.

In some specific examples of the method of the present invention, the blending step (step (a)) includes three steps: the first step includes combining the API (which is preferably screened/sieved) with part of the filler (and any antioxidants) ) Blending to form an API premix; the second step includes blending glidants (which are preferably screened/sieved), disintegrants, and any binders with the API premix to form the main blend And the third step includes adding a lubricant (which is preferably co-screened with part of the main blend) to the main blend and then The resulting mixture is blended. In some embodiments, no water or solvent is used in the blending step, that is, no water or solvent is added during the blending step.

A typical manufacturing method using a three-stage blending step is described in further detail below. Typically, no water or solvent is used in the three-stage blending step, that is, no water or solvent is added in the three-stage blending step.

The API is first screened through a sieve (such as a hand sieve). A premix containing the API ("API premix") is prepared by blending the screened API with part of the filler. If the antioxidant is one of the components, the antioxidant can be blended into the API premix to ensure that the antioxidant is thoroughly mixed with the API.

The glidant is screened through a sieve to remove clumps. Then all other components including the sieving glidant, except the lubricant, are added, and the API premix is sandwiched between the powder mass. The resulting mixture ("main blend") is blended to form a blended powder ("main blend").

The lubricant is co-screened with a small portion of the main blend, and then the co-screened mixture is added to the main blend. This lubrication step can be performed separately in order to avoid possible problems caused by excessive lubrication (such as reducing tablet hardness or decomposition events).

The resulting mixture is mixed to form a powder blend. After blending, the blended powder is compressed to form a solid core.

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

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

The solid core can be sub-coated with a polymer known in the art to be suitable for sub-coating prior to coating with the enteric film coating.

The solid core is coated with an enteric film coating, for example, by spray coating with an enteric film coating dispersion. The enteric film coating dispersion is prepared, for example, by dispersing the enteric film coating polymer in deionized water or an organic solvent, mixing the dispersion, and then sieving through a sieve. The desired amount or thickness of the enteric film coating on the solid core is achieved by standard methods known in the art, such as by controlling the spray rate of the enteric film coating dispersion, and controlling the solid core to remain in the coating. The length of time on the plate, control the inlet temperature, control the drum speed, or atomization air pressure.

Instance

The present invention is further illustrated by referring to the following non-limiting examples.

Substances and methods

All the materials used to make the illustrated pharmaceutical composition were purchased from commercial sources.

Sodium metaarsenite ("SMA") was obtained from Sigma Aldrich Fine Chemicals. As supplied, the SMA drug showed extremely high purity (>98% As(III)) and the lowest concentration of As(V). Table 1 below provides the characteristics of the supplied SMA drugs.

Table 1: Characteristics of SMA drugs supplied

The substances listed in Table 2 below were used to make 2.5 mg sodium metaarsenite ("SMA") enteric film-coated tablets. If possible, try to choose a higher-density main excipient to match SMA (an inorganic substance with an estimated true density of about 2.1 to 2.3g/cm ^-3 , which is very dense compared to most excipients ) The density.

The equipment listed in Table 3 below was used to manufacture and analyze the SMA enteric film coating composition.

Manufacturing example 1

The enteric film-coated tablets of formulation examples 1.1 to 1.4 contain sodium metaarsenite ("SMA") as the active pharmaceutical ingredient (API), which is manufactured according to the following process.

Generally, and as detailed below, sodium metaarsenite ("SMA") and excipients are blended together (in a three-stage blending process, no water or solvent is used) to form a powder blend. The powder blend is then compressed to form the solid core of the tablet. Then the solid core of the tablet is coated with an enteric film coating.

Blending

The following blending process is used to blend the components.

Divide and weigh the API and other components of the composition. Since the concentration of the API is very low, try to use a three-stage blending process (using "API premix" and "main mix") to improve the blending uniformity.

The API is screened through a 200 μm sieve (hand sieve). The sieving time is between 5-8 minutes.

A premix containing API (the "API premix") is obtained by placing the selected API and several grams (20 grams for 500g batches and 30 grams for 700g batches) filler in a suitable container ( It is prepared by blending with a 100ml container for a 500g batch and a 150ml container for a 700g batch at 49 rpm using a Turbula blender for 10 minutes.

The glidant (colloidal silica) is screened through a 500μm sieve to remove clumps. Then add all other dispersed components including the sieve glidant, except for the lubricant (sodium stearyl fumarate), to a 2L glass Turbula tank, and the API premix is sandwiched in the powder mass intermediate. The glidant is screened through a sieve to remove clumps.

The resulting mixture ("main blend") is blended using a Turbula blender at 49 rpm for between about 10 to about 20 minutes to form a blended powder ("main blend").

The lubricant (sodium stearyl fumarate) and a small portion of the main blend were co-screened using a 500 μm sieve, and then the co-screened mixture was added to the main blend. This lubrication step can be performed separately in order to avoid possible problems caused by excessive lubrication (such as reducing tablet hardness or decomposition events).

The resulting mixture was mixed in a Turbula blender at 49 rpm for 2 minutes to form a powder blend. Determine the flow characteristics of the powder blend.

suppress

The powder blend was pressed on a Manesty F3 single-punch tablet press using a 6.5mm Normal Concave Platform (NCCP) die to form a tablet with a target weight of 150mg. The Manesty F3 has only arbitrary unit (AU) of pressing force, and it is impossible to directly measure the applied force. The target hardness degree is greater than 90N.

Enteric coating

20% w/w solid content enteric film coating dispersion is prepared by dispersing Acryl-EZE II white (493Z180022) in deionized water. Before use, the dispersion was stirred with a paddle stirrer for 45 minutes throughout the coating process. Before use, the dispersion was sieved through a 250 μm sieve.

Before inserting the solid core of the tablet, the 15" coating pan (Thai Coater) was equilibrated to the set point temperature. Due to the small batch size, the'inert filler' was added to the API solid core to satisfy the The loading requirements of the coating pan. Before coating, the solid core of the tablet is equilibrated in the drying pan for 10 minutes. Use the same temperature and airflow in the heating, coating and drying phases. Put the coated tablet in After coating, it was dried in the pan for 10 minutes. The samples were collected after the weight increased by 8, 10 and 12% w/w.

Dissolution research

A 500 mL medium and USP Method 2 (paddle) were used for dissolution studies at an initial paddle speed of 100 rpm. A single group of six enteric film-coated tablets (n=6) was used for testing. After 2 hours in the acid, the dissolution medium sample was withdrawn and the sodium meta-arsenite concentration was measured to evaluate the resistance of the stomach. Replace the medium with a pH 6.8 phosphate buffer, and withdraw the sample within a 15-minute interval to produce a dissolved state.

This method is based on the pharmacopoeial method (EP.2.9.3 and USP<711>) according to the enteric solvent quantity type as shown in Table 4 below.

Deployment example 1.1

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

The composition was prepared on a 700 g scale. Collect blending uniformity and content uniformity samples to analyze the homogeneity after the main blending time 20 minutes.

Table 5 below provides the composition (before the coating step) of the solid core of the tablet containing 2.53 mg of sodium metaarsenite. ( Table 5.1 below provides another possible composition (before the coating step) of the solid core of the tablet containing 2.50 mg sodium metaarsenite.

According to the blending step, the powder blend proved to have good flow characteristics as indicated by the Carr Index (29.3%). The powder blend has the following characteristics before pressing:

˙Inflation density: 0.64g/cm ³

˙Tap density: 0.91g/cm ³

˙Carr index: 29.3%

˙Hausner Ratio: 1.30

Throughout the process, it was observed that the powder was extremely compressed without weight change and/or visual separation The end blend. It achieves high tablet hardness (104.8N) and low friability (0.08%), and the disintegration time (34 seconds) is relatively fast. The average thickness of the solid core of the tablet is 3.63 mm.

Samples for blending uniformity were sampled after 20 minutes of blending, and samples for content uniformity were collected at the beginning, middle and end of the pressing process. The results of blending uniformity showed excellent uniformity and the relative standard deviation (RSD)% value was 1.3. The content uniformity of the solid core of the tablet during the compression process (initial, intermediate and final) shows good uniformity, because the maximum acceptable value (AV) value <7.4 (AV value <15 is acceptable).

According to the compression step, the solid core of the tablet is coated with the Acryl-EZE II white (493Z180022) enteric film-coated polymer system, which is manufactured as described in Manufacturing Example 1. The film coating parameters are shown in Table 6 below.

The enteric film-coated tablet showed an acceptable dissolution state (500ml medium, paddle speed 100rpm). After 120 minutes, the composition was intact in an acidic medium (pH 1.0) and released 0% API. After 135 minutes of pH 6.8, 91% of the API was released. After 150 minutes of pH 6.8, 98% of API is released. After pH 6.8 reaches 165 minutes, 100% of API is released.

The enteric-coated film-coated tablets have been proven to meet gastric tolerance and meet the recommended preliminary specifications, that is, at least 75% of the tablets will be released within 45 minutes in the enteric formulation.

Table 5.1 below provides other possible compositions (before the coating step) of the solid core of the tablet containing 2.50 mg sodium metaarsenite. The solid core having the composition described in Table 5.1 can be prepared in a similar manner to the solid core having the composition described in Table 5 above. And meet the recommended preliminary specifications, that is, insoluble in 75% enteric solvent type within 45 minutes.

Deployment example 1.2

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

The composition is prepared on a 500 gram scale. Blending uniformity samples were collected after the main blending time of 10, 15 and 20 minutes. The blend is compressed to form the solid core of the tablet, and then the solid core of the tablet is coated.

Table 7 below provides the composition (before the coating step) of the solid core of the tablet containing 2.50 mg sodium metaarsenite.

Table 7: The composition of the solid core of P23 tablets

According to the blending step, the powder blend proved to have good flow characteristics (26.37%) as indicated by the Carr Index. The powder blend has the following characteristics before pressing:

˙Inflation density: 0.67g/cm ³

˙Tap density: 0.91g/cm ³

˙Carr index: 26.37%

˙Hausner Ratio: 1.36

˙Resting angle: 24.32°

Samples of blending uniformity were collected after blending for the main blending time of 10, 15 and 20 minutes. The composition showed good homogeneity at a blending time of 20 minutes.

Use 6.5mm NCCP tool to press on Manesty F3 single punch. The average solid core hardness is 94.3N, the average thickness is 3.62mm, the fragility is 0.33%, and the disintegration time is 39 seconds.

The weight of the solid core is consistent throughout the entire pressing process and is made into an acceptable solid core. No visible split was observed. Samples (two sets of 10 solid cores) were collected at the beginning, middle and end of the pressing process and sent for content uniformity testing.

According to the pressing step, the solid core of the tablet is coated with the Acryl-EZE II white (493Z180022) enteric film-coated polymer system, which is manufactured as described in Manufacturing Example 1, and is due to weight increase Collect samples after 8, 10 and 12% w/w. The film coating parameters are shown in Table 8 below .

The enteric film-coated tablets with weight increase of 8%, 10% and 12% w/w were tested for dissolution (500ml dissolution medium, paddle speed 75rpm) to determine the appropriate degree of enteric film coating. The dissolution results are shown in Table 9 below .

Table 9: Dissolution results

The enteric film-coated tablet is intact after 120 minutes in an acidic medium. The enteric-coated film-coated tablets have been proven to meet gastric tolerance and meet the recommended preliminary specifications, that is, at least 75% of the tablets will be released within 45 minutes in the enteric formulation.

According to the dissolution results, it was found that the film coating increased weight by 12% w/w as the best.

Deployment example 1.3

The solid pharmaceutical composition (P31) containing sodium metaarsenite (SMA) as the active pharmaceutical ingredient (API) was manufactured using the method described in Manufacturing Example 1.

The composition system was prepared on a 500g scale. Samples of blending uniformity were collected after the main blending time of 10, 15 and 20 minutes. The blend is compressed to form the solid core of the tablet, and then the solid core of the tablet is coated. L-hydroxypropyl cellulose (L-HPC; low-substituted hydroxypropyl cellulose LH-B1 grade) is used because it acts as a binder and disintegrant. Since L-HPC is insoluble in water, it is estimated that hard tablets will be obtained.

Table 10 below provides the composition of the solid core of the tablet containing 2.50 mg sodium metaarsenite (before the coating step).

According to the blending step, the powder blend proved to have good flow characteristics as indicated by the Karl index (23.68%). The powder blend has the following characteristics before pressing:

‧Inflation density: 0.58g/cm ³

˙Tap density: 0.76g/cm ³

˙Carr index: 23.68%

˙Hausner Ratio: 1.31

˙Angle of rest: 27.96°

Samples of blending uniformity were collected after the main blending time of 10, 15 and 20 minutes. The composition showed good uniformity at a blending time of 20 minutes.

Use 6.5mm NCCP tool to press on Manesty F3 single punch. The average solid core hardness is 104.3N, the average thickness is 3.52mm, the fragility is 0.23%, and the disintegration time is 30 seconds.

The weight of the solid core is consistent throughout the entire pressing process and is made into an acceptable solid core. No visible split was observed. Samples (two sets of 10 solid cores) were collected at the beginning, middle and end of the pressing process and sent for content uniformity testing.

According to the pressing step, the solid core of the tablet is coated with the Acryl-EZE II white (493Z180022) enteric film-coated polymer system, which is manufactured as described in Manufacturing Example 1, and increases in weight by 8 Collect samples after 10 and 12% w/w. The film coating parameters are shown in Table 11 below .

The enteric film-coated tablets with weight increase of 8%, 10% and 12% w/w were tested for dissolution (500ml dissolution medium, paddle speed 75rpm) to determine the appropriate degree of enteric film coating. The dissolution results are shown in Table 12 below .

An enteric film-coated tablet with a weight gain of 8% w/w failed the acid resistance test. Enteric film-coated tablets with a weight increase of 10% w/w and enteric film-coated tablets with a weight increase of 12% w/w have been shown to meet gastric tolerance and meet the recommended preliminary specifications, that is, in the enteric type 45 Release at least 75% within minutes.

According to the dissolution results, it was found that the film coating increased weight by 12% w/w as the best.

Deployment example 1.4

The solid pharmaceutical composition (P66) containing sodium metaarsenite (SMA) as the active pharmaceutical ingredient (API) was manufactured as described in Manufacturing Example 1.

The composition system is manufactured on a 700 g scale. Samples of blending uniformity and content uniformity were collected after 20 minutes of the main blending time to evaluate the uniformity.

Table 13 below provides the composition (before the coating step) of the solid core of the tablet containing 2.53 mg of sodium metaarsenite.

According to the blending step, the powder mixture proved to have good flow characteristics as indicated by the Carr index (25.74%). The powder mixture has the following characteristics before pressing:

˙Inflation density: 0.75g/cm ³

˙Tap density: 1.01g/cm ³

˙Carr index: 25.74%

˙Hausner Ratio: 1.35

Throughout the entire pressing process, the powder blend was excellently pressed and no weight change and/or visually visible splitting were observed throughout the entire pressing process. Achieve high solid core hardness (87.4N) and low friability (0.11%), and the disintegration time (2 minutes 52 seconds) is relatively fast. The average thickness of the solid core is 3.66mm.

Samples for blending uniformity were sampled after 20 minutes of blending, and samples for content uniformity were collected at the beginning, middle and end of the pressing process. The results of blending uniformity showed excellent uniformity, with a% relative standard deviation (RSD) value of 2.1. The content uniformity of the solid core of the tablet in the entire pressing process (initial, intermediate and final) shows good uniformity, because the maximum acceptable value (AV) value <6.3 (AV value <15 is acceptable) .

According to the compression step, the solid core of the tablet is coated with the Acryl-EZE II white (493Z180022) enteric film-coated polymer system, which is manufactured as described in Manufacturing Example 1. The film coating parameters are shown in Table 14 below .

The enteric film-coated tablet exhibits an acceptable dissolution profile (500ml medium, paddle speed 100rpm). After 120 minutes, the composition released 0% API in an acidic medium (pH 1.0). After 135 minutes of pH 6.8, 21% of API was released. After 150 minutes of pH 6.8, release 86% of the API. After 165 minutes at pH 6.8, 96% of API was released. After 195 minutes of pH 6.8, 98% of API is released.

The enteric-coated film-coated tablets have been proven to meet gastric tolerance and meet the recommended preliminary specifications, that is, at least 75% of the tablets will be released within 45 minutes in the enteric formulation.

Manufacturing example 2

Table 15 below provides an enteric film-coated tablet composition containing 2.5 mg of sodium metaarsenite as the active pharmaceutical ingredient (API). The enteric film-coated tablet is prepared using the following method.

Typically, and as detailed below, the sodium metaarsenite ("SMA") and excipients are blended together (a two-stage blending process, no water or solvent is used) to form a powder blend. The powder blend is then compressed to form the solid core of the tablet. The solid core of the tablet is then coated with an enteric film coating.

Blending

The following blending process is used to blend the components.

The API and other components of the composition are distributed and weighed. Because the concentration of API is very low, try to use a two-stage blending process (using "API premix" and "main mix") to improve the blending uniformity.

The API is sieved through a 106 μm sieve (the sieving time is about 5 to 8 minutes).

A part of the dibasic calcium phosphate is added to the sieved API, and the resulting mixture is blended for 30 minutes to obtain an "API premix".

Then the API premix is blended with the remaining dibasic calcium phosphate and other excipients (silicified microcrystalline cellulose, sodium starch glycolate, colloidal silica, and sodium stearyl fumarate), And get the "main mixture". The main mixture was blended with an accelerator bar for 4 minutes to obtain a powder blend.

suppress

The powder blend was compressed into a target tablet weight of 150 mg ± 5% (range 142.5-157.5 mg) in a Key International lozenge machine using a 0.25 inch tool. Dust the solid core.

The final solid core proved to have no significant friability (0.00%) and a hardness of 156.9N (16kp).

Enteric coating

The 25% w/w solid content enteric film coating dispersion is produced by dispersing Acryl-EZE green powder in deionized water. The dispersion was stirred for about 30 minutes (until uniform).

The dedusted solid core is spray-coated (350 g/min) with the dispersion to increase the weight by about 10 to 12% w/w. The disk speed is about 6-8 rpm. The film-coated tablet is dried after coating.

It should be understood that if any known art publication is mentioned in this article, these references do not constitute the general knowledge part of the art of this publication in Australia or any other country.

In the following patent claims and the foregoing description of the present invention, unless otherwise required in the context due to the language of expression or necessary implication, the word "comprising" or variants such as "including" or "covering" is meant to include Sexual use means specifying the existence of the feature, but does not exclude other features that are present or added in various specific examples of the present invention.

Claims (33)

A pharmaceutical composition suitable for oral administration, comprising: (a) a solid core comprising sodium meta-arsenite or potassium meta-arsenite, and the following pharmaceutically acceptable excipients: (i) filling Agent or diluent, which ranges from about 5 to 95% w/w, (ii) disintegrant, which ranges from about 10 to 90% w/w, (iii) glidant, which ranges from about 0.1 to 5% w/w, (iv) a lubricant, which ranges from about 0.1 to 5% w/w, and (v) a suitable adhesive, which ranges from 0 to about 30% w/w; and (b) An enteric film coating containing an enteric polymer; wherein the pharmaceutically acceptable excipient is selected to minimize the oxidation of metaarsenite to metaarsenate, wherein the intestine The weight percentage of the film coating is from about 6% w/w to about 20% w/w based on the total weight of the pharmaceutical composition, and the thickness of the film coating is from about 6.5% to about 15% of the thickness of the pharmaceutical composition . The medical composition according to claim 1, wherein the amount of sodium meta-arsenite or potassium meta-arsenite in the solid core is about 0.1 to 5.0% w/w of the solid core. The medical composition according to claim 1 or 2, wherein the solid core contains sodium metaarsenite. The medical composition according to any one of claims 1 to 3, wherein the filler or diluent is present in the solid core of the medical composition in an amount of about 10 to 90% w/w of the solid core . The medical composition according to any one of claims 1 to 4, wherein the filler or diluent is selected from the group consisting of binary anhydrous calcium hydrogen phosphate, partially pregelatinized starch, silicified microcrystalline cellulose, microcrystalline cellulose, Calcium sulfate dihydrate, lactose, calcium hydrogen phosphate, calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, or mixtures thereof. The medical composition according to claim 5, wherein the filler or diluent is dibasic anhydrous calcium hydrogen phosphate, partially pregelatinized starch, or a mixture thereof. The medical composition according to any one of claims 1 to 6, wherein the disintegrant is present in the solid core of the medical composition in an amount of about 10 to 50% w/w of the solid core. The medical composition according to any one of claims 1 to 7, wherein the disintegrant is selected from L-hydroxypropyl cellulose, partially pregelatinized starch, cross-linked polyvinylpyrrolidone, potato starch, corn starch, Sodium starch glycolate, and alginic acid. The pharmaceutical composition according to claim 8, wherein the disintegrant is L-hydroxypropyl cellulose, partially pregelatinized starch, sodium starch glycolate, or a mixture of two or more of them. The medical composition according to any one of claims 1 to 9, wherein the glidant is present in the solid core of the medical composition in an amount of about 0.3 to 4.0% w/w of the solid core. The medical composition according to any one of claims 1 to 10, wherein the glidant is selected from colloidal silica and talc. The pharmaceutical composition according to claim 11, wherein the glidant is colloidal silica. The medical composition according to any one of claims 1 to 12, wherein the lubricant is present in the solid core of the medical composition in an amount of about 0.3 to 4.0% w/w of the solid core. The medical composition according to any one of claims 1 to 13, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, stearic acid, talc, and silicon dioxide. The pharmaceutical composition according to claim 14, wherein the lubricant is sodium stearyl fumarate. The medical composition according to any one of claims 1 to 15, which further comprises a binder in an amount of about 1 to 30% w/w of the solid core, wherein the binder is selected from silicified microcrystalline cellulose , Microcrystalline cellulose, partially pregelatinized starch, L-hydroxypropyl cellulose (low-substituted hydroxypropyl cellulose), hydroxypropyl cellulose, povidone (polyvinylpyrrolidone), pregelatinized corn starch , Hydroxypropyl methylcellulose, starch, gum arabic, corn starch, and gelatin. The medical composition according to claim 16, wherein the binder is L-hydroxypropyl cellulose (low-substituted hydroxypropyl cellulose), L-hydroxypropyl cellulose (low-substituted hydroxypropyl cellulose) And a mixture of hydroxypropyl cellulose, or partially pregelatinized starch. The pharmaceutical composition according to any one of claims 1 to 17, wherein the enteric film coating provides a solid core weight increase of about 7 to 17% w/w. The pharmaceutical composition according to any one of claims 1 to 18, wherein the enteric film coating polymer is selected from copolymers of acrylic acid and its esters or methacrylic acid or its esters, polysorbate, Cellulose acetate phthalate polymer, hydroxypropyl methyl cellulose phthalate polymer, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, vinyl acetate Triacid cellulose, carboxymethyl ethyl cellulose, and shellac. The pharmaceutical composition according to claim 19, wherein the enteric film coating polymer is a copolymer of methacrylic acid and ethyl acrylate (1:1). The medical composition according to any one of claims 1 to 20, wherein the solid core comprises sodium metaarsenite, binary anhydrous calcium hydrogen phosphate, L-hydroxypropyl cellulose, hydroxypropyl cellulose, colloid Silicon dioxide, and sodium stearyl fumarate. The medical composition according to any one of claims 1 to 20, wherein the solid core comprises sodium metaarsenite, binary anhydrous calcium hydrogen phosphate powder, partially pregelatinized starch, binary anhydrous calcium hydrogen phosphate, hydroxyl Sodium starch acetate, colloidal silica, and sodium stearyl fumarate. The medical composition according to any one of claims 1 to 20, wherein the solid core comprises sodium metaarsenite, binary anhydrous calcium hydrogen phosphate powder, binary anhydrous calcium hydrogen phosphate, L-hydroxypropyl cellulose , Sodium starch glycolate, colloidal silica, and sodium stearyl fumarate. The medical composition according to any one of claims 1 to 20, wherein the solid core comprises sodium metaarsenite, binary anhydrous calcium hydrogen phosphate, partially pregelatinized starch, sodium starch glycolate, colloidal silica , And sodium stearyl fumarate. The medical composition according to any one of claims 1 to 20, wherein the solid core comprises sodium metaarsenite, binary anhydrous calcium hydrogen phosphate, silicified microcrystalline cellulose, sodium starch glycolate, and colloidal silica , And sodium stearyl fumarate. The medical composition according to any one of claims 1 to 20, wherein the medical composition is an enteric film-coated tablet comprising a solid core of 1.67% w/w sodium metaarsenite and having The diameter of the solid core is about 6.5mm, the mass of the solid core is 150mg, and the enteric coating of the solid core is about 12% w/w. The medical composition according to any one of claims 1 to 26, which is used to treat a disease or condition, wherein the disease or condition is selected from solid malignant tumor, bone metastasis, metastatic tumor disease, primary or metastatic Lung tumors, genitourinary system cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune diseases, immune diseases, diabetic retinopathy, diabetic angiopathy, diabetic neuralgia, and pancreatic islets Symptoms related to inflammation and ulcerative colitis. A method of manufacturing a pharmaceutical composition according to any one of claims 1 to 26, the method comprising the following steps: (a) The active pharmaceutical ingredient (API) selected from sodium meta-arsenite and potassium meta-arsenite is blended with the following pharmaceutically acceptable excipients to form a powder blend: (i) filler or A diluent, which ranges from about 5 to 95% w/w, (ii) a disintegrant, which ranges from about 10 to 90% w/w, and (iii) a glidant, which ranges from about 0.1 to 5% w/w, (iv) lubricant, which ranges from about 0.1 to 5% w/w, and (v) any binder, which ranges from 0 to about 30% w/w; (b) The powder blend formed in step (a) is compressed to form a solid core; and (c) the solid core is coated with an enteric film coating containing an enteric polymer; wherein the pharmaceutically acceptable The excipients are selected so that the oxidation of metaarsenite to metaarsenate can be minimized, wherein the weight percentage of the enteric film coating is about 6% w/ relative to the total weight of the pharmaceutical composition w to about 20% w/w, and wherein the thickness of the film coating is about 6.5% to about 15% of the thickness of the pharmaceutical composition. The method according to claim 28, wherein step (a) includes two steps: (i) blending API with a part of filler to form an API premix; and (ii) the glidant and disintegrant , Lubricant and any adhesives are blended with API premix. The method according to claim 28, wherein step (a) includes two steps: (i) blending the API with a part of the filler to form an API premix; (ii) the glidant and disintegrant And any binders are blended with the API premix; and then (iii) a lubricant (which is optionally mixed with a portion of the mixture from step (ii)) is added, and then blended. The method according to any one of claims 28 to 30, wherein no water or solvent is added in step (a) and/or step (b). A method for treating a disease or condition in an individual, which comprises orally administering the pharmaceutical composition according to any one of claims 1 to 26 to the individual, wherein the disease or condition is selected from solid malignant tumors, bone metastases, Metastatic tumor disease, primary or metastatic lung tumor, genitourinary system cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disease, immune disease, diabetic retinopathy, Diabetic vascular disease, diabetic neuralgia, symptoms related to insulitis, and ulcerative colitis. A use of the pharmaceutical composition according to any one of claims 1 to 26 in the preparation of an oral medicine for treating a disease or condition, wherein the disease or condition is selected from solid malignant tumor, bone metastasis, metastatic tumor disease , Primary or metastatic lung tumors, genitourinary system cancer, leukemia, pain, blood cancer, metastatic cancer, cancer pain, chronic pain, inflammation, autoimmune disease, immune disease, diabetic retinopathy, diabetic vascular disease, Diabetic neuralgia, symptoms associated with insulitis and ulcerative colitis.