Naltrexone Compositions

Abstract

The present invention is a single-unit oral dose pharmaceutical composition comprising a first active ingredient for absorption in the esophagus and beyond and a second active ingredient for absorption in the oral cavity, the first active ingredient being naltrexone in an amount of 0.01-10 mg and the second active ingredient being calcitriol in an amount of 80-200 μg. The pharmaceutical composition is particularly effective in the treatment of cancer.

Description

[Technical field]

[0001] The present invention is directed to single-unit oral dosage pharmaceutical compositions comprising naltrexone for use in the treatment of various disorders, such as cancer. [Background technology]

[0002] Co-administration of adjuvant-type molecules predicts the success of many cancer treatments: even without any independent therapeutic benefit, the adjuvant serves to prime the subject's immune system so that the active compound targeted to the cancer can achieve maximum therapeutic effect.

[0003] Adjuvants typically modulate the immune response of patients, so they are most commonly used in combination with cancer treatments or biologics such as humanized therapeutic antibodies. They act to boost the patient's immune system to increase antibody production in response to a challenge with a cancer treatment, or to suppress or reduce the patient's immunogenicity to foreign therapeutic antibodies. Thus, adjuvants play an important role in driving cancer immunotherapy toward a successful treatment outcome.

[0004] Immunotherapy is often combined with more traditional cancer treatments such as radiation therapy or chemotherapy. In certain types of cancer for which no effective immunotherapy exists, traditional treatments alone may be administered. Traditional cancer treatments may also be administered in combination, and the therapeutic effect of co-administration may be greater than the sum of the effects of the individual administrations.

[0005] Despite greater efficacy, the combination of traditional cancer therapies can exacerbate the side effects experienced by patients, often resulting in premature termination of treatment regimens. Thus, the beneficial synergistic effects of co-administering multiple anticancer drugs may not be achieved due to the harsh nature of this treatment. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003) [Non-Patent Document 2] Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000) Summary of the Invention [Problem to be solved by the invention]

[0007] The development of new treatments with greater efficacy and reduced side effects would obviate the need for co-administration of certain cancer therapeutics, avoiding harsh side effects that often lead to premature treatment termination. Alternatively, the development of adjuvant-like molecules that amplify the therapeutic efficacy of chemotherapeutic drugs would achieve a similar outcome.

[0008] Thus, there is a need to develop agents that enhance the therapeutic utility of chemotherapeutic drugs in order to minimize the deleterious side effects of chemotherapeutic drugs that otherwise constitute aggressive cancer treatment regimens.

[0009] Furthermore, such drugs need to be administered to patients in a manner that maximizes therapeutic efficacy and minimizes any adverse effects or problems. Oral dosage forms, such as tablets or capsules, that are swallowed by patients are commonly used. However, one significant limitation is the lack of bioavailability of the active ingredient through this administration route (i.e., by swallowing).

[0010] There is therefore a need to develop agents that enhance the therapeutic utility of chemotherapeutic drugs in formulations that maximize the bioavailability of the active ingredient. [Means for solving the problem]

[0011] According to a first aspect of the present invention, there is provided a single-unit oral dosage pharmaceutical composition comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0012] According to a second aspect of the present invention there is provided a single unit oral dose pharmaceutical composition for use as a medicament comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0013] According to a third aspect of the present invention there is provided a single unit oral dose pharmaceutical composition for use in treating cancer in a subject comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0014] According to a further aspect of the present invention, a method for producing a method for manufacturing a semiconductor device comprising the steps of: - providing a first formulation comprising between 0.01 and 10 mg of naltrexone; - providing a second formulation in contact with the first formulation, the second formulation being a solution, suspension or emulsion comprising 80-200 μg of calcitriol; - optionally freezing the combination of the first formulation and the second formulation; - freeze-drying the combination of the first formulation and the second formulation; There is provided a method for forming a single unit oral dosage pharmaceutical composition according to the present invention, comprising: [Brief description of the drawings]

[0015] [Figure 1A] FIG. 1A shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug oxaliplatin on HCT116 (colon cancer) cell count. [Figure 1B] FIG. 1B shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug oxaliplatin on HCT116 (colon cancer) cell viability. [Figure 2A] FIG. 2A shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug oxaliplatin on A549 (lung cancer) cell number. [Figure 2B] FIG. 2B shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug oxaliplatin on A549 (lung cancer) cell viability. [Figure 3A] FIG. 3A shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug gemcitabine on HCT116 (colon cancer) cell count. [Figure 3B] FIG. 3B shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug gemcitabine on HCT116 (colon cancer) cell viability. [Figure 4A] FIG. 4A shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug gemcitabine on A549 (lung cancer) cell number. [Figure 4B]FIG. 4B shows the effect of naltrexone (LDN) and calcitriol (CCT) in combination with the chemotherapy drug gemcitabine on A549 (lung cancer) cell viability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] A single-unit oral dosage pharmaceutical composition comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the gastrointestinal tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01 to 10 mg, and the second active ingredient is calcitriol in an amount of 80 to 200 μg. The present inventors have discovered that single unit oral dosage pharmaceutical compositions are optimized for delivery of active ingredients for therapeutic benefit, particularly when used as agents to enhance the therapeutic benefit of anti-cancer drugs.

[0017] It has been found that a combination of naltrexone and calcitriol in a single unit oral dose can be administered to patients as part of cancer treatment, regardless of renal or hepatic function. This has the advantage that patients can be prescribed a single unit dose without the need for pre-screening for renal or hepatic function / insufficiency. Thus, physicians can be confident that an adequate dose of medication is being prescribed with minimal potential side effects.

[0018] The inventors have realized the benefits of combining low doses of naltrexone and calcitriol in a form that provides different absorption rates so that the ingredients act in a synergistic manner to support the desired therapeutic effect.

[0019] The single unit oral dosage of the present invention allows for different optimized delivery routes of the two active ingredients, i.e., CCT is absorbed in the oral cavity and naltrexone is absorbed beyond the oral cavity, i.e., after being swallowed by the patient, through the esophagus and further into the digestive tract, which the inventors have found to result in improved bioavailability of the active ingredients.

[0020] The inventors have achieved this improved bioavailability in a single unit dose that is simple and convenient for patients to take, thus leading to improved patient compliance.

[0021] Calcitriol is a metabolite of vitamin D. The normal metabolic process of vitamin D is that it is first converted to calcifediol (CCD) in the liver, which can then be converted to calcitriol (CCT) in the kidney. CCD has a long half-life and persists in the blood. However, when CCT is needed, CCD is converted to CCT in the kidney. This essentially means that the concentration of CCT is kept relatively constant through tightly controlled regulation by the body. Typically, plasma concentrations are maintained at around 60 pg / ml. Due to this regulatory process, increasing vitamin D supplementation does not tend to significantly increase CCT concentrations.

[0022] Certain cancer patients may have impaired kidney and liver function. Certain cancer cells may be involved in the CY They have an increase in P enzyme, which means that vitamin D metabolism is impaired. Specifically, CCT cannot be converted from precursor CCD, because CCT cannot be converted from vitamin D. In addition, patients with liver or kidney cancer may also be unable to metabolize vitamin D in the normal way, so CCT cannot be converted.

[0023] Therefore, the inventors have identified that it is desirable to administer CCT, rather than vitamin D, specifically to cancer patients.

[0024] However, the inventors have noted that CCT has variable bioavailability, i.e., plasma concentration may vary, when swallowed by a patient, for example in tablet form. This variability means that the desired dosage may not be achieved. One way to alleviate this problem is to increase the dosage per tablet to provide a maximum dose limit. However, by doing this, there is a risk of causing kidney damage from toxicity.

[0025] The single-unit oral dosage of the present invention allows CCT to be absorbed in the oral cavity, which has been found to have a more consistent delivery of CCT.Furthermore, the single-unit oral dosage of the present invention allows naltrexone to be absorbed beyond the oral cavity, i.e., from the esophagus to the gastrointestinal tract, which provides optimal naltrexone delivery.

[0026] The inventors have therefore identified a composition optimized for the delivery of active ingredients in the treatment of cancer, particularly in conjunction with the use of anti-cancer drugs, which can be easily administered to patients as a single unit oral dose while maximizing the bioavailability of the active ingredient.

[0027] In a first aspect of the present invention, there is provided a single-unit oral dosage pharmaceutical composition comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0028] The term "pharmaceutical composition" as used herein means a mixture containing a specified amount, e.g., a therapeutically effective amount, of a therapeutic compound or compounds in a pharma- ceutical acceptable carrier, for administration to a mammal, e.g., a human, to treat a disease.

[0029] As used herein, the term "pharmaceutical acceptable" refers to those compounds, materials, compositions and / or dosage forms that are within the bounds of sound medical judgment and are suitable for contact with mammalian, especially human, tissue, free from undue toxicity, irritation, allergic response and other significant complications, and commensurate with a reasonable benefit / risk ratio.

[0030] The term "single unit oral dose" as used herein has its usual meaning in the art. It may also be referred to as an oral dosage form. It may be, for example, a tablet, a coated tablet, a bilayer tablet, a multilayer tablet, a caplet, a capsule, a disk, a pellet, or a granule.

[0031] The single unit oral dosage pharmaceutical composition comprises naltrexone as a first active ingredient.

[0032] As used herein, "naltrexone" refers to morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-(5α), whose empirical formula is 20 H 23 NO4, whose molecular weight is 341.41 in amorphous form. (Maximum moisture content less than 1%). The chemical structure of naltrexone is:

[0033] [ka]

[0034] It is.

[0035] The single unit oral dosage pharmaceutical composition contains naltrexone in an amount of 0.01-10 mg. Preferably, the single unit oral dosage contains 0.1 mg-6 mg, more preferably 1 mg-5 mg, and most preferably 3-4.5 mg of naltrexone. This dosage of naltrexone has been found to be particularly effective in acting in conjunction with anti-cancer agents.

[0036] The single unit oral dose pharmaceutical composition is formulated such that the first active ingredient, naltrexone, is for absorption in the esophagus and beyond the digestive tract. This means that naltrexone is absorbed in the esophagus, stomach, small intestine, or large intestine (i.e., the digestive tract following its natural course, starting from the esophagus) for delivery to the bloodstream. Naltrexone is not substantially absorbed in the patient's oral cavity.

[0037] Absorption of naltrexone from the esophagus and beyond the gastrointestinal tract is achieved by patients swallowing a single unit dose.

[0038] The single unit oral dosage pharmaceutical composition comprises calcitriol as a second active ingredient.

[0039] As used herein, "calcitriol" refers to the active metabolite of vitamin D, specifically vitamin D3. Calcitriol is also called 1,25-dihydroxyvitamin D3 or 1,25-dihydroxycholecalciferol. Its empirical formula is: 27 H 44 O3. Its chemical structure is:

[0040] [ka]

[0041] It is.

[0042] The single unit oral dosage pharmaceutical composition contains calcitriol in an amount of 80-200 μg. Preferably, the single unit oral dosage contains 90-190 μg, more preferably 100-180 μg, and most preferably 110-170 μg. The dosage of naltrexone has been found to be particularly effective in acting in conjunction with anti-cancer agents.

[0043] The single unit oral dose containing 80-200 μg of calcitriol provides a systemic (serum) concentration of calcitriol of 0.1-10 ng / ml, more preferably 2-8 ng / ml, and most preferably 4-6 ng / ml.

[0044] The single unit oral dose pharmaceutical composition is formulated so that the second active ingredient, calcitriol, is available for absorption in the oral cavity, the term oral cavity having its ordinary meaning in the art and including the mouth, lips, hard palate, soft palate, retromolar trigone, tongue, gingiva (gums), oral mucosa (mucosa inside the lips and cheeks), and floor of the mouth under the tongue.

[0045] Absorption of calcitriol in the oral cavity may be achieved by sublingual, sublabial, gingival, or buccal routes.

[0046] In a preferred embodiment, a single unit oral dose pharmaceutical composition according to the present invention comprises naltrexone in a first formulation and calcitriol in a second formulation. The first and second formulations are separate from each other, i.e., not mixed. The first formulation is typically a tablet formulation, and the second formulation allows for the release and subsequent absorption of calcitriol in the oral cavity.

[0047] The term formulation is intended to encompass a mixture of active ingredient(s) with any pharma- ceutically acceptable excipient.

[0048] In a preferred embodiment, the first formulation containing naltrexone is formulated as a tablet, capsule, powder, disc, caplet, granules or pellets.

[0049] Preferably, the tablets, capsules, powders, disks, caplets, granules or pellets are administered intravenously. It is administered orally and swallowed by the subject, meaning that the subject swallows the tablet, capsule, powder, disk, caplet, granules or pellets, which are then metabolized via the traditional pathway, i.e., through the esophagus and beyond in the digestive tract.

[0050] Tablets, capsules, powders, discs, caplets, granules or pellets may be provided as a blend of the naltrexone product with a combination of pharma- ceutically acceptable excipients. As used herein, the term "excipient" refers to pharma- ceutically acceptable raw materials commonly used in the pharmaceutical arts for the preparation of solid oral dosage formulations. Examples of excipient classes include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. The amount of each excipient used may vary within ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms, all of which are incorporated herein by reference. See, J. D. Pharmacol. 2001, 143: 1111-1123, and J. D. Pharmacol. 2001, 143: 1111-1123, all of which are incorporated herein by reference.

[0051] Suitable excipients include magnesium carbonate, magnesium stearate, talc, lactose, lactose monohydrate, sugar, pectin, dextrin, starch, tragacanth, microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, corn starch, anhydrous colloidal silica, titanium dioxide, a low melting wax, cocoa butter, and the like.

[0052] The first formulation may include ingredients that allow for immediate or sustained release of the first active ingredient naltrexone in the gastrointestinal tract beyond the esophagus. This may be achieved by including a pharma- ceutically acceptable rate-controlling polymer. The rate-controlling polymer may be hydrophilic or hydrophobic. Preferably, the rate-controlling polymer is selected from polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethylcellulose, fatty acids, fatty acid esters, alkyl alcohols, microcrystalline cellulose, poly(meth)acrylates, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, gum arabic, gellan gum, locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, carboxyvinyl polymers, polymerized gelatin, and / or mixtures thereof.

[0053] The second active ingredient, calcitriol, is formulated for absorption in the oral cavity. In a preferred embodiment, the second formulation containing calcitriol is formulated for absorption by the sublingual route. Absorption in the oral cavity can be achieved by any known method. For example, it can be formulated in an oral disintegrating form that disintegrates and dissolves in the mouth without water before swallowing. It can be dissolved in this manner within 60 seconds, preferably within 10 seconds.

[0054] Preferably, the second formulation containing calcitriol is an orally disintegrating tablet or coating, an orally dispersible tablet or coating, an orally dissolving tablet or coating, a rapid dissolving tablet or coating, a fast melt tablet or coating, a rapid disintegrating tablet or coating, or a freeze-dried wafer.

[0055] Orally disintegrating tablets / coatings are solid dosage forms that contain a pharmaceutical agent and disintegrate rapidly (within seconds) without water when placed on the tongue. The drug is released, dissolved, or dispersed in saliva.

[0056] Rapidly dissolving tablets / coatings (also known as rapid dissolving tablets, rapid dissolving multiparticulate tablets, immediate dissolution tablets, orodissolving tablets, fast melt tablets, or orodispersible tablets) are designed to be easily swallowed. It is a water-free solid dosage form. The tablet dissolves in the mouth within 60 seconds. The active ingredient is absorbed through the mucous membrane of the mouth.

[0057] The freeze-dried wafers are fast-dissolving, thin matrices containing the pharmaceutical agent (in this case, calcitriol) without the need for water for swallowing. The wafers instantly disintegrate in the oral cavity, releasing the calcitriol, which dissolves or disperses in the saliva.

[0058] The second formulation may be administered to a subject sublingually, sublabially or buccally by rapidly dissolving in the mouth upon contact with saliva. Preferably, it is absorbed sublingually.

[0059] The second formulation containing calcitriol may be formulated by known methods such as lyophilization (freeze drying), cotton candy process, molding, sublimation, and direct compression. In a preferred embodiment, the second formulation containing calcitriol is formulated as a lyophilized dosage form. Preferably, it is a lyophilized solution, suspension, or emulsion. The second formulation is achieved by any known method for producing a dosage form that dissolves in the oral cavity, such as by utilizing the following technologies: Zydis®, QuickSolv®, Lyoc®, Flashdose, OraSolve, Ziplet technology, Frosta, DuraSolve, Wowtab, Durasolv, Flashtab®, Oraquick, RapiTab, and Nanomelt (by Elan).

[0060] The inventors have found that patients who absorb calcitriol in the oral cavity overcome the various bioavailability problems that occur when calcitriol is swallowed in a tablet. Calcitriol has various bioavailability when swallowed, which means that the desired dosage cannot be achieved. One way to alleviate this problem is to increase the dosage per tablet to provide a maximum dose limit. However, doing this risks causing kidney damage from toxicity. The inventors have found that administering calcitriol to the oral cavity achieves the desired dosage without causing any adverse symptoms associated with kidney damage, such as fatigue, loss of appetite, or swelling of the legs. Absorption in the oral cavity also avoids drug metabolism through the stomach and intestines, which means more efficient calcitriol delivery.

[0061] The second formulation containing calcitriol may also contain any conventional or pharma- ceutical suitable excipients suitable for providing absorption in the oral cavity, such as ingredients that dissolve rapidly in saliva and contribute to rapid disintegration in the mouth.

[0062] Preferred ingredients can include a matrix forming agent and a sugar or sugar alcohol. These ingredients are used to provide sufficient strength to the unit dose to prevent breakage during removal and packaging, but they allow for rapid dissolution of the formulation once placed in the mouth.

[0063] Preferred matrix forming agents include gelatin, starch, modified starch, maltodextrin, cellulose gum, carrageenan gum, hyaluronic acid, pectin, sodium carboxymethylcellulose, agar, gelatin gum, guar gum, tragacanth gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carbomer, poloxamer, polyacrylic acid, polyvinyl alcohol, alginate, and polyglyconic acid, or combinations thereof.

[0064] Preferred sugar alcohols include mannitol, sorbitol, glycerol, erythritol, and glycerol. Examples of suitable glycerols include maltitol, lactitol and lactitol, or combinations thereof.

[0065] Preferred sugars include trehalose, dextrose and lactose, or combinations thereof.

[0066] In a preferred embodiment, the second formulation comprises gelatin and / or mannitol.

[0067] The second formulation, preferably containing calcitriol, is formed by cryogenically freezing a liquid, emulsion or suspension containing calcitriol and optional additives. The frozen units are then subjected to a lyophilization process in a freeze dryer. During lyophilization, numerous air pockets are created which aid in the absorption of saliva and aid in the breakdown of the layers, meaning that the layers can be rapidly absorbed in the oral cavity.

[0068] In a preferred embodiment, the first formulation containing naltrexone is in the form of a tablet, and the second formulation containing calcitriol is a lyophilized solution, suspension or emulsion that is attached to the tablet, thus forming a single-unit oral dose. The first formulation and the second formulation are preferably two separate and distinct parts of a single-unit oral dose pharmaceutical composition. The second formulation may be attached to the tablet by any known means. For example, the second formulation may coat the tablet, or it may be formed as a layer, film or wafer connected to or on the tablet.

[0069] One of skill in the art may utilize any known method for producing a single unit oral dosage form that includes a first formulation and a second formulation.

[0070] In a preferred embodiment, the single-unit oral dosage pharmaceutical composition comprises a first formulation containing naltrexone in tablet form and a second formulation containing calcitriol as a lyophilized solution, suspension or emulsion attached to the tablet, thus forming a single-unit oral dosage. In this embodiment, the first formulation containing naltrexone in tablet form is formulated for delayed release. Delayed release means that naltrexone is released after being swallowed by the patient. This ensures that naltrexone is absorbed primarily in the esophagus and beyond in the digestive tract, i.e., in the stomach. Furthermore, the second formulation containing calcitriol is a lyophilized solution, suspension or emulsion attached to the tablet, ensuring that calcitriol is absorbed in the oral cavity.

[0071] Additionally, in a preferred embodiment, the first formulation containing naltrexone is formulated to be released and / or absorbed after the second formulation containing calcitriol, meaning that the calcitriol is formulated such that it is released and / or absorbed before the naltrexone is released and / or absorbed by the patient.

[0072] According to a further aspect of the present invention, a method for producing a method for manufacturing a semiconductor device comprising the steps of: - providing a first formulation comprising between 0.01 and 10 mg of naltrexone; - providing a second formulation in contact with the first formulation, the second formulation being a solution, suspension or emulsion comprising 80-200 μg of calcitriol; - optionally freezing the combination of the first formulation and the second formulation; - freeze-drying the combination of the first formulation and the second formulation; The present invention provides a method for forming a single unit oral dosage pharmaceutical composition comprising:

[0073] In a preferred embodiment, (i) providing a first formulation comprising between 0.01 and 10 mg of naltrexone; (ii) compressing the first blend into a tablet, capsule, powder, disc, caplet, granule, or pellet; (iii) providing a second formulation comprising 80-200 μg of calcitriol, the second formulation being a solution, suspension or emulsion; (iv) casting the second formulation into a preformed mold and optionally freezing the second formulation; (v) adding the first formulation to the preformed mold such that the first formulation contacts the second formulation; (vi) lyophilizing the combination of the first formulation and the second formulation; There is provided a method for forming a single unit oral dosage pharmaceutical composition according to the present invention, comprising:

[0074] In a preferred embodiment, the first step is the formulation of a mixture containing 0.01-10 mg of naltrexone. The mixture may be made by any known method, such as dry granulation or wet granulation. The mixture may optionally contain a filler, a glidant, a disintegrant and / or a lubricant. The mixture is preferably compressed into a tablet capsule, powder, disk, caplet, granule or pellet.

[0075] In a next step, a second formulation containing 80-200 μg of calcitriol is formulated as a solution, suspension or emulsion. The second formulation optionally contains a matrix forming agent and / or a sugar or sugar alcohol, preferably mannitol and gelatin.

[0076] Preferably, the second blend is then poured into a preformed mold. In a next step, the first blend is attached to the second blend and the combination of blends is frozen. This may be achieved by placing a preformed tablet in contact with the second blend into the mold. The freezing step is preferably carried out quickly, for example for a period of 1 to 10 minutes, using a very low temperature, for example below -70°C. The combination of blends may be frozen by any suitable method known in the art, but preferably it is cryogenically frozen.

[0077] The final step is lyophilization of the frozen formulation combination, also called freeze-drying. Preferably, the lyophilization process is carried out in a freeze-drying chamber operating under a vacuum of typically 0.1-1.0 hPa (0.1-1.0 mbar) for a period of 180-500 minutes.

[0078] In a preferred embodiment, the single unit oral dosage pharmaceutical composition has a weight ratio of calcitriol to naltrexone in the range of 1:1 to 10:1, which ratio range has been found to provide superior levels of activity in the treatment of cancer.

[0079] In a preferred embodiment, the single unit oral dosage composition comprises a third active ingredient. Preferably, the third active ingredient is present in a third formulation. The third formulation can be made by the methods described above for the first and second formulations.

[0080] In a preferred embodiment, the third active ingredient is a cannabinoid. The cannabinoid is selected from the list consisting of cannabidiol, cannabidiol acid, cannabinol, tetrahydrocannabivarin, arachidonoylethanolamine, cannabidivarin, 2-arachidonoylglycerol, cannabigerol, cannabivarin, cannabichromene, 2-arachidonoylglyceryl ether, N-arachidonoyldopamine, virodamine, dronabinol, nabilone, rimonabant, or combinations thereof.

[0081] In a preferred embodiment, the third active ingredient is a flavonoid, preferably a flavonoid found in cannabis, such as cannaflavin-A, cannaflavin-B, cannaflavin-C, quercetin, isovitexin, apigenin, beta-sitosterol, luteolin, orientin, catechin, vitexin, silymarin, kaempferol, or combinations thereof.

[0082] In a preferred embodiment, the third active ingredient is a terpene. Preferably, the terpene is a terpene found in cannabis, such as limonene, linalool, myrcene, pinene, phytol, terpinolene, trans-nerolidol, valencene, humulene, geraniol, eucalyptol, delta-3-carene, caryophyllene, camphene, borneol, bisabolol, or combinations thereof.

[0083] In a second aspect of the present invention, there is provided a single unit oral dose pharmaceutical composition for use as a medicament, comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0084] The single unit oral dosage pharmaceutical composition for pharmaceutical use may have any of the preferred features described above.

[0085] The single-unit oral dose pharmaceutical composition for use as a medicine is particularly suitable for subjects with reduced ability to metabolize vitamin D, since such subjects are unable to metabolize vitamin D in the normal manner to form calcitriol. The administration of calcitriol in a single-unit oral dose according to the present invention overcomes this problem.

[0086] In a third aspect of the present invention, there is provided a single unit oral dose pharmaceutical composition for use in treating cancer in a subject comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0087] The single unit oral dosage pharmaceutical composition for use in treating cancer in a subject may have any of the preferred features described above. The single unit oral dosage pharmaceutical composition may be used as a cancer treatment, but primarily it is used to amplify the effect of anti-cancer drugs.

[0088] The term "subject" as used herein refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, dogs, cats, rodents, and the like, that is the recipient of a treatment in which a pharmaceutical composition comprising a single unit dose is used according to the present invention. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0089] The term "treatment" as used herein refers to a therapeutic measure that cures, slows down the progression of, and / or stops a diagnosed pathological condition or disorder. In some cases, a subject is successfully "treated" with the present invention for tumor / cancer when it shows one or more of the following: reduction in the number or complete absence of cancer cells; reduction in tumor size; inhibition or absence of cancer cell invasion into surrounding organs, such as the spread of cancer cells to soft tissue and bone; inhibition or absence of tumor metastasis; inhibition or absence of tumor growth; reduction in morbidity and mortality; reduction in tumorigenicity, tumor incidence or tumorigenic potential of tumors; reduction in the number or frequency of cancer stem cells in tumors; differentiation of tumorigenic cells into non-tumorigenic state; or some combination of effects.

[0090] The term "cancer" as used herein refers to any tissue mass resulting from excessive cell growth, proliferation and / or survival, either benign (non-cancerous) or malignant (cancerous), including pre-cancerous lesions. The terms "cancer", "tumor" and "neoplasm" may be used interchangeably. Tumors and cancers include benign, malignant, metastatic and non-metastatic types, and any stage (I, II, III, IV or V) or grade (G1, G2, G3, etc.) of tumor or cancer or metastasis that is progressing, worsening, stable or in remission.

[0091] The single unit oral dose pharmaceutical composition according to the present invention may be used to treat any cancer, such as carcinoma, lymphoma, blastoma, sarcoma, and leukemia; more specific examples of such tumors / cancers include squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, carcinoma of the peritoneum, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, melanoma, vulvar cancer, thyroid cancer, liver cancer, as well as various types of head and neck cancer.

[0092] In a preferred embodiment, the single-unit oral dose pharmaceutical composition for use according to the present invention is used to treat subjects with liver and / or kidney cancer.The present invention is particularly beneficial for subjects with kidney and / or liver cancer, because such subjects may have reduced kidney and liver function and therefore cannot metabolize vitamin D to form CCT in the normal way.

[0093] In a preferred embodiment, the single-unit oral dose pharmaceutical composition for use in the treatment of cancer is used for subjects with reduced ability to metabolize vitamin D. This is because such subjects cannot metabolize vitamin D in the usual way to form calcitriol. Certain cancer cells have an increase in CYP enzymes, which means that vitamin D metabolism is impaired, specifically, CCT cannot be converted from precursor CCD, since CCD cannot be converted from vitamin D. The administration of calcitriol in a single-unit oral dose according to the present invention overcomes this problem.

[0094] In a preferred embodiment, the single unit oral dose pharmaceutical composition is used to treat a subject undergoing or selected to undergo treatment with an anti-cancer drug. The inventors have discovered that the single unit dose of naltrexone and calcitriol according to the present invention is a suitable booster or primer for the anti-cancer drug, thus reducing the dose of the anti-cancer drug.

[0095] As used herein, "anti-cancer agent" has its conventional meaning as used in the art. For purposes of the present invention, the term chemotherapeutic agent is encompassed by the phrase "anti-cancer agent."

[0096] In a preferred embodiment, the anti-cancer agent is a PI3 kinase inhibitor, an AKT inhibitor, a taxane, an antimetabolite, an alkylating agent, a cell cycle inhibitor, a topoisomerase inhibitor, and a cytotoxic agent. The anti-cancer agent may be selected from the group consisting of anti-cancer antibodies. The anti-cancer agent may be administered by any conventional method, which depends largely on the small molecule signaling inhibitor used. Thus, administration by parenteral, oral, sublingual, nasal and / or pulmonary routes, among others, is envisaged.

[0097] When the anti-cancer agent is a PI3 kinase inhibitor, suitable examples include, but are not limited to, wortmannin, LY294002, demethoxyviridin, IC87114, NVP-BEZ235, BAY80-6946, BKM120, GDC-0941, GDC-9080; combinations thereof; and pharma- ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs of any of the above.

[0098] When the anti-cancer agent is an AKT inhibitor, suitable examples include, but are not limited to, MK-2206, GSK690693, perifosine, PHT-427, AT7867, honokiol, PF-04691502; combinations thereof; and pharma- ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs of any of the above.

[0099] When the anti-cancer agent is a taxane, suitable examples include, but are not limited to, paclitaxel and docetaxel; combinations thereof; and pharma- ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs of any of the above.

[0100] When the anticancer agent is an antimetabolite, suitable examples include, but are not limited to, methotrexate, 5-fluorouracil, capecitabine, cytosine arabinoside (cytarabine), gemcitabine, 6-thioguanine, pentostatin, azathioprine, 6-mercaptopurine, fudarabine, and cladribine; combinations thereof; and pharma- ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs of any of the above. Gemcitabine is a particularly preferred antimetabolite. For example, gemcitabine is available at a dose of 800-1200 mg / m 2 , preferably 900 to 1100 mg / m 2 , for example about 1000 mg / m 2 or 1000 mg / m 2 may be administered in doses (per dose).

[0101] When the anticancer agent is an alkylating agent, suitable examples include, but are not limited to, mechlorethamine, cyclophosphamide, ifosfamide, trofosfamide, melphalan (L-sarcolysin), chlorambucil, hexamethylmelamine, thiotepa, busulfan, carmustine (BCNU), streptozocin (streptozotocin), dacarbazine (DTIC; dimethyltriazenoimidazole carboxamide), temozolomide, and oxaliplatin; combinations thereof; and pharma- ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs of any of the above. Cyclophosphamide and oxaliplatin are particularly preferred alkylating agents. For example, oxaliplatin is administered at a dose of 65-105 mg / m 2 , preferably 75 to 95 mg / m 2 , for example about 85 mg / m 2 , or 85 mg / m 2 By way of example, cyclophosphamide may be administered at a dose of 1800 mg / m 2 up to, for example, 400-1800 mg / m 2 may be administered in doses (per dose).

[0102] When the anti-cancer drug is a cell cycle inhibitor, suitable examples include epothilones, vincristine, vinblastine, UCN-01, 17AAG, XL844, CHIR-124, PF-00477736, CEP-3891, flavopiridol, berberine, P276-00, terameprocol, isoflavone daidzein, BI2536, BI6727, GSK461364, cyclaporine, ON-01910, NMS-P937, TAK-960, ispinesib, monastrol, AZD4877, LY2523355, ARRY-52 0, MK-0731, SB743921, GSK923295, lonafarnib, proTAME, bortezomib, MLN9708, ONX0912, CEP-18770; combinations thereof; and pharma- ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs of any of the above; particularly suitable examples of cell cycle inhibitors include, but are not limited to, hesperadin, ZM447439, VX-680, MLN-8054, PHA-739358, AT-9283, AZD1152, MLN8237, ENMD2076, SU6668; combinations thereof; and pharma-ceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs of any of the above.

[0103] In certain embodiments, the anti-cancer agent is an antimetabolite, preferably gemcitabine.

[0104] In certain embodiments, the anticancer agent is an alkylating agent, preferably oxaliplatin.

[0105] In a preferred embodiment, the anti-cancer agent may be a checkpoint inhibitor, which is an agent that acts at a surface protein that is a member of either the TNF receptor or the B7 superfamily, including agents that bind to negative co-stimulatory molecules selected from CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3, and / or their respective ligands, such as PD-L1 (Mellman et al., supra).

[0106] In a preferred embodiment, the anti-cancer agent is a cannabinoid. Preferably, the cannabinoid is selected from the list consisting of cannabidiol, cannabidiolic acid, cannabinol, tetrahydrocannabivarin, arachidonoylethanolamine, cannabidivarin, 2-arachidonoylglycerol, cannabigerol, cannabivarin, cannabichromene, 2-arachidonoylglyceryl ether, N-arachidonoyldopamine, virodamine, dronabinol, nabilone, rimonabant, or a combination thereof.

[0107] In a preferred embodiment, the anti-cancer agent is a flavonoid, preferably a flavonoid found in cannabis, such as cannaflavin-A, cannaflavin-B, cannaflavin-C, quercetin, isovitexin, apigenin, beta-sitosterol, luteolin, orientin, catechin, vitexin, silymarin, kaempferol, or combinations thereof.

[0108] In a preferred embodiment, the anti-cancer agent is a terpene. Preferably, the terpene is a terpene found in cannabis, such as limonene, linalool, myrcene, pinene, phytol, terpinolene, trans-nerolidol, valencene, humulene, geraniol, eucalyptol, delta-3-carene, caryophyllene, camphene, borneol, bisabolol, or combinations thereof.

[0109] In a preferred embodiment, the single unit oral dose pharmaceutical composition will be administered to a subject in a first treatment phase, and after the first treatment phase, the subject will be administered a therapeutically effective amount of an anti-cancer agent in a second treatment.

[0110] In a preferred embodiment, the administration regimen of the single unit dose pharmaceutical composition for use according to the present invention is daily administration of a single unit dose.

[0111] In a fourth aspect of the present invention, there is provided a single-unit oral dose pharmaceutical composition for use in treating an autoimmune disease in a subject, comprising a first active ingredient and a second active ingredient. is provided, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0112] In a preferred embodiment, the autoimmune disease is psoriasis, systemic lupus erythematosus (SLE) or thyroiditis.

[0113] The present invention also relates to the use of a single-unit oral dose pharmaceutical composition comprising a first active ingredient and a second active ingredient for the manufacture of a medicament, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0114] The single unit oral dosage pharmaceutical composition may have any of the preferred features described above.

[0115] The present invention also relates to the use of a single unit oral dose pharmaceutical composition comprising a first active ingredient and a second active ingredient for the manufacture of a medicament for use in the treatment of cancer, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0116] The single unit oral dosage pharmaceutical composition may have any of the preferred features described above.

[0117] The present invention also relates to a method of treating cancer in a subject comprising administering to the subject a single unit oral dose pharmaceutical composition comprising a first active ingredient and a second active ingredient, The first active ingredient is for absorption in the esophagus and beyond the digestive tract; The second active ingredient is for absorption in the oral cavity; The first active ingredient is naltrexone in an amount of 0.01-10 mg, and the second active ingredient is calcitriol in an amount of 80-200 μg.

[0118] This embodiment of the invention may have any of the preferred features described above. EXAMPLES

[0119] Example 1: Synthesis of a single unit dose according to the present invention A single unit dose pharmaceutical composition according to a preferred embodiment of the present invention was prepared as follows: Tablets containing naltrexone (LDN) were formulated with the following ingredients:

[0120] [Table 1]

[0121] The formulation was initially a dry mix that was compressed into 100 mg tablets having a crystalline coating with the CCT formulation attached.

[0122] The CCT formulation was formulated from a solution or suspension containing 140 μg CCT, gelatin, and mannitol.

[0123] The liquid / suspension is added to a preformed blister, and then the LDN tablet is attached to form a single unit dose, which is then passed through a cryogenic freezing process. The frozen units then undergo a lyophilization process in a freeze dryer. The blisters containing the dried units are then sealed via a heat sealing process to protect the product from various environmental conditions and ensure long-term stability.

[0124] Example 2: Administration of Naltrexone (LDN) and Calcitriol (CCT) in Combination with Chemotherapeutic Agents Cancer cell lines A549 (lung) or HCT116 (colon) were cultured at 1.5 × 10 4 Cells were reset at a density of 100 / ml and allowed to adhere to 6-well plates for 4 hours. Cells were then subjected to a regimen consisting of two treatment phases, each lasting 48 hours. In the first phase, cells were cultured with either 10 nM naltrexone (LDN) or 10 nM naltrexone and 10 nM CCT (LDN+CCT or LDNC). At the end of this first phase, the exhausted medium was replaced with fresh medium. Then, a second treatment phase consisting of either 1 μM gemcitabine (GEM) or 500 nM oxaliplatin (OXP) was applied. At the end of the treatment, cells were detached with trypsin and cell number and % viability were assessed by cell counting using the trypan blue dye exclusion method, which helps to identify non-viable cells.

[0125] These studies demonstrated that the combination of naltrexone and calcitriol was more effective at amplifying the effects of the chemotherapy drugs gemcitabine and oxaliplatin than naltrexone alone. (See Figures 1A, 1B, 2A, 2B, 3A, 3B, 4A, and 4B.)

Claims

1. A single-unit oral dosage pharmaceutical composition comprising a first active ingredient and a second active ingredient, the first active ingredient is for absorption in the esophagus and beyond the gastrointestinal tract; the second active ingredient is for absorption in the buccal cavity; The first active ingredient is naltrexone in an amount of 0.01 to 10 mg, and the second active ingredient is calcitriol in an amount of 80 to 200 μg. A single unit oral dose pharmaceutical composition.

2. 10. The single unit oral dosage pharmaceutical composition of claim 1 comprising between 0.01 mg and 6 mg of naltrexone.

3. A single-unit oral dosage pharmaceutical composition as described in claim 1, containing between 3 and 4.5 mg of naltrexone.

4. 4. A single unit oral dosage pharmaceutical composition according to any one of claims 1 to 3, comprising naltrexone in a first formulation and calcitriol in a second formulation.

5. 5. The single unit oral dosage pharmaceutical composition of claim 4, wherein the first formulation containing naltrexone is formulated as a tablet, capsule, powder, disc, caplet, granule, or pellet.

6. 6. The single unit oral dosage pharmaceutical composition of claim 4 or 5, wherein the second formulation containing calcitriol is formulated for sublingual absorption.

7. 7. The single unit oral dose pharmaceutical composition of claim 6, wherein the second formulation containing calcitriol is formulated as a solution, suspension, or emulsion that has been frozen and lyophilized.

8. The first formulation containing naltrexone is in tablet form and contains calcitriol.

5. The single unit oral dose pharmaceutical composition of claim 4, wherein the second formulation is a lyophilized and frozen solution, suspension or emulsion attached to the tablet.

9. 10. The single unit oral dosage pharmaceutical composition of claim 8, wherein the first formulation containing naltrexone in tablet form is formulated for delayed release.

10. 9. The single-unit oral dosage pharmaceutical composition of claim 8, wherein the first formulation comprising naltrexone is released and / or absorbed after the second formulation comprising calcitriol is released and / or absorbed.

11. 11. The single unit oral dosage pharmaceutical composition of any one of claims 1 to 10, wherein the weight ratio of calcitriol to naltrexone is in the range of 1:1 to 10:

1.

12. A single-unit oral dose pharmaceutical composition according to any one of claims 1 to 11, further comprising a cannabinoid, a flavonoid, and / or a terpene.

13. Cannabidiol, cannabidiolic acid, cannabinol, tetrahydrocannabivarin, arachidonoylethanolamine, cannabidivarin, 2-arachidonoylglycerol, cannabigerol, cannabivarin, cannabichromene, 2-arachidonoylglyceryl ether, N-arachidonoyldopamine, virodamine, dronabinol, nabilone, rimonabant, cannaflavin-A, cannaflavin-B, cannaflavin-C, quercetin, isovitexin, apigenin, beta-sitosterol, luteolin 12. The single unit oral dose pharmaceutical composition of any one of claims 1 to 11, further comprising a cannabinoid, flavonoid, and / or terpene selected from the group consisting of: orientin, catechin, vitexin, silymarin, kaempferol, limonene, linalool, myrcene, pinene, phytol, terpinolene, trans-nerolidol, valencene, humulene, geraniol, eucalyptol, delta-3-carene, caryophyllene, camphene, borneol, bisabolol, and combinations thereof.

14. A single unit oral dosage pharmaceutical composition according to any one of claims 1 to 13 for use as a medicine.

15. A single unit oral dosage pharmaceutical composition according to any one of claims 1 to 13 for use in treating cancer in a subject.

16. 16. A single unit oral dose pharmaceutical composition for use according to claim 15, wherein the subject is undergoing or is selected to undergo treatment with an anti-cancer agent.

17. 17. A single-unit oral dose pharmaceutical composition for use according to claim 15 or 16, wherein the subject has liver cancer and / or kidney cancer and / or the subject has a reduced ability to metabolise vitamin D.

18. 18. The single-unit oral dose pharmaceutical composition for use according to any one of claims 15 to 17, wherein the single-unit oral dose pharmaceutical composition is to be administered to the subject in a first treatment phase, and after the first treatment phase, the subject is to be administered a therapeutically effective amount of an anti-cancer agent in a second treatment.

19. The single-unit oral dose pharmaceutical composition for use according to any one of claims 15 to 18, wherein said administration regimen is daily administration of a single-unit dose.

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