Formulations comprising triethylenetetramine tetrahydrochloride

Abstract

This invention relates to pharmaceutical formulations comprising triethylenetetramine tetrahydrochloride (TETA.4HCl). Specifically, it relates to pharmaceutical compositions suitable for once-daily administration to subjects in therapeutic need.

Description

Technical Field

[0001] This invention relates to pharmaceutical formulations comprising triethylenetetraminetetrahydrochloride (TETA.4HCl). Specifically, it relates to pharmaceutical compositions suitable for once-daily administration to subjects requiring treatment. Background Technology

[0002] Triethylenetetramine, or 1,2-ethylenediamine, N,N'-bis(2-aminoethyl) (also known as trientine or TETA), has the following structure:

[0003]

[0004] Trientine is a copper (II) polyamine chelator. Its copper-chelating properties make it suitable for treating a variety of conditions, particularly Wilson's disease (also known as Wilson's disease). Wilson's disease is a hereditary disorder caused by mutations in the Wilson's disease protein (ATP7B gene). This disease leads to the accumulation of copper in the body. Trientine's copper-chelating ability has also led to its consideration for treating various conditions, such as visceral organ damage in diabetic patients, Alzheimer's disease, and cancer (Henriet et al., International Journal of Pharmaceutics 511 (2016) 312-321). Trientine tetrahydrochloride (TETA.4HCl) is a particularly advantageous trientine salt for treating Wilson's disease, but dihydrochloride (TETA.2HCl) is also used.

[0005] Trientine (whether as tetrahydrochloride or dihydrochloride) is typically administered multiple times daily to patients in need of treatment for better control of copper levels. However, lifelong multiple-day dosing can be challenging, often leading to poor patient adherence due to strict food-related timing requirements, particularly for asymptomatic or stable conditions such as maintenance therapy for Wilson's disease (WD) (Ala et al., Dig. Dis. Sci 60 (2015) 1433-1439). Once-daily dosing of trientine would improve patient adherence by minimizing the significant challenges currently faced by WD patients in adhering to daily food intake or other concomitant medication requirements. Improved adherence to WD treatment may slow disease progression and improve treatment outcomes in patients with Wilson's disease.

[0006] However, despite the need to develop a once-daily tricentine formulation, no once-daily formulation has been developed and is currently used in the clinical treatment of Wilson's disease. This is at least partly due to the challenges of developing a suitable oral dosage form. Specifically, most existing oral tricentine formulations contain only a maximum of about 200 mg of tricentine, requiring patients to take a large dose at once to reach the recommended dose of up to about 1,500 mg / day. Trientine formulations containing higher concentrations of tricentine are known, but these are very large oral dosage forms (especially capsules), making them difficult for patients to swallow. For example, TETA 2HCl capsules (National Drug Codes 16571-810-01, 16571-812-05) containing 250 mg or 500 mg of TETA 2HCl (equivalent to about 167 mg or 333 mg of tricentine, respectively) are known. The 250 mg capsule is a "size 1" capsule, 19.4 mm in length and 6.9 mm in diameter. In contrast, the 500 mg capsule containing twice the amount of active ingredient is a "00" capsule, which is 23.3 mm long and 8.6 mm in diameter.

[0007] Furthermore, tablets are generally preferred over capsules because they typically exhibit greater storage stability and are easier to divide into multiple doses. However, increasing the amount of active ingredient in tablets without significantly increasing tablet size is not straightforward. Tablets need to be reformulated to produce a formulation containing fewer excipients overall to provide more active ingredient, while still containing a sufficient variety and appropriate amount of excipients to provide acceptable pharmaceutical properties. These properties include compression characteristics during manufacturing, such as friability (or hardness), brittleness, and strength, as well as pharmacokinetic characteristics, such as bioavailability (e.g., measured using area under the curve) and dissolution rate / disintegration time. In particular, the physicochemical interactions between the active ingredient and excipients can make achieving such acceptable pharmaceutical properties at high active ingredient loadings challenging. For example, not all copper antagonists potentially suitable for treating Wilson's disease can be formulated at high active ingredient loadings while still maintaining the aforementioned acceptable pharmaceutical properties.

[0008] To improve patient compliance with once-daily dosing, there is a need to provide oral formulations of trientamin with higher concentrations of the active ingredient to reduce the number of dosage forms that need to be taken simultaneously, without significantly increasing the dosage form size (palatability) and maintaining optimal characteristics for drug administration. Summary of the Invention

[0009] The inventors have surprisingly discovered that, by using specific formulation ingredients, triethylenetetramine tetrahydrochloride can be formulated into tablets with very high levels of triethylenetetramine tetrahydrochloride (i.e., up to 95 wt% relative to the total weight of the tablet) while still maintaining optimal (or even improved) properties for drug administration (e.g., size, fragility, bioavailability / area under curve, and dissolution rate / disintegration time). Therefore, this formulation is more suitable for once-daily administration than known tricentine dihydrochloride or tetrahydrochloride formulations (which contain up to about 50 wt% tricentine hydrochloride). Furthermore, advantageously, the size of this formulation is not significantly larger than known TETA 4HCl tablets and significantly smaller than known TETA 2HCl capsules providing similar amounts of active ingredient.

[0010] Specifically, the inventors have discovered that tablets containing up to 95 wt% triethylenetetramine tetrahydrochloride can be prepared by reducing the amount of filler in the composition while still providing rapid dissolution and bioavailability. More specifically, the inventors have discovered that direct compression tablets containing up to 95 wt% TETA 4HCl can be prepared while maintaining controllable size and performance in terms of bioavailability, disintegration, and mechanical strength. This supports once-daily dosing for patients with Wilson's disease and improves adherence, and enables individualized dosing (e.g., pediatric dosing via tablet splitting). Clinical pharmacokinetic studies have shown that the once-daily dosing formulation has significantly better AUC and Cmax values ​​than the twice-daily dosing formulation, and no safety issues were observed.

[0011] Therefore, the present invention provides a tablet dosage form comprising: 60 to 95 wt% of triethylenetetramine tetrahydrochloride; and 0.1 to 10 wt% of a first lubricant; wherein the wt% amount is relative to the total weight of the tablet.

[0012] The present invention also provides a tablet dosage form as described herein for the prevention or treatment of Wilson's disease in a subject. Attached Figure Description

[0013] Figure 1 Image of a tablet core containing 85 wt% TETA 4HCl (relative to tablet core weight).

[0014] Figure 2 Image of a coated tablet containing 82.2 wt% TETA 4HCl (relative to the total weight of the tablet).

[0015] Figure 3 The study design of the bioavailability study compared the new once-daily dosing formulation with the original twice-daily dosing formulation. Detailed Implementation

[0016] definition

[0017] The formulation of the present invention comprises triethylenetetramine tetrahydrochloride, also referred to herein as trientine tetrahydrochloride or TETA.4HCl.

[0018] The tablet dosage form is referred to as tablet in this article.

[0019] As used herein, the term “about” means the value ±5%, preferably the value ±2%.

[0020] Unless otherwise stated, all percentages mentioned herein are weight percentages (wt%). Wt% is relative to the total weight of the tablets. In the case of coated tablets, the total weight of the tablets is the weight of the coated tablets.

[0021] As used herein, unless otherwise specified, references to “triethylenetetramine” or “triethylenetetramine active ingredient” in a composition refer to the weight of the free triethylenetetramine base in the composition. If the weight refers to the salt of triethylenetetramine (particularly the weight of triethylenetetramine tetrahydrochloride), this will be clearly stated.

[0022] TETA.4HCl tablets

[0023] The present invention provides a tablet dosage form comprising 60 to 95 wt% of triethylenetetramine tetrahydrochloride relative to the total weight of the tablet. Preferably, the content of triethylenetetramine tetrahydrochloride in the tablet is 70 to 95 wt% (e.g., 75 to 95 wt%, or 76 to 95 wt%, or 77 to 95 wt%, or 78 to 95 wt%, or 79 to 95 wt%, or 80 to 95 wt%), more preferably 70 to 90 wt%, more preferably 75 to 90 wt% (e.g., 76 to 90 wt%, or 77 to 90 wt%, or 78 to 90 wt%, or 79 to 90 wt%), even more preferably 80 to 90 wt%, and even more preferably 80 to 85 wt%.

[0024] Triethylenetetramine tetrahydrochloride may be present in tablets in an amount of about 600 mg, thus providing a dose of 300 mg of the active ingredient triethylenetetramine (i.e., triethylenetetramine base) (the remainder by weight being hydrochloride). Alternatively, triethylenetetramine tetrahydrochloride may be present in tablets in an amount of about 100 mg to about 600 mg (i.e., about 50 mg to about 300 mg triethylenetetramine base), for example, about 100 mg to about 400 mg (i.e., about 50 mg to about 200 mg triethylenetetramine base) or about 100 mg to about 200 mg (i.e., about 50 mg to about 100 mg triethylenetetramine base). Tablets containing lower amounts of triethylenetetramine tetrahydrochloride may be particularly suitable for pediatric use.

[0025] Triethylenetetramine tetrahydrochloride can be provided in any suitable form. For example, triethylenetetramine tetrahydrochloride can be crystalline triethylenetetramine tetrahydrochloride. Triethylenetetramine tetrahydrochloride is known to exist in at least two different polymorphic forms, referred to as polymorph A and polymorph B, as described in WO 2019 / 211464, for example. Polymorph A and polymorph B can be characterized by their XRPD spectra (e.g., using Cu-Kα X-ray radiation measurements with a characteristic wavelength (λ) of 1.5418 Å), as described in WO 2019 / 211464. Polymorph A and polymorph B can be characterized alternatively or additionally by their Raman spectra. Polymorph A and polymorph B can be characterized alternatively by any additional techniques (e.g., FTIR analysis) described in WO 2019 / 211464.

[0026] For example, a typical characteristic of crystal form A, triethylenetetramine tetrahydrochloride, is that its XRPD spectrum has peaks at 25.2 and 35.7 ± 0.1° 2θ, typically at 25.2 and 35.7 ± 0.05° 2θ. Preferably, the XRPD spectrum of crystal form A also has peaks at 21.8, 26.9, and 28.2 ± 0.1° 2θ, typically at 21.8, 26.9, and 28.2 ± 0.05° 2θ.

[0027] A typical characteristic of crystalline form B triethylenetetramine tetrahydrochloride is that its XRPD spectrum has at least two, at least three, at least four, at least five, or all of the peaks selected from 22.9, 25.4, 25.8, 26.6, 34.6, and 35.3 ± 0.1° 2θ. More preferably, the XRPD spectrum of crystalline form B has at least two peaks selected from 22.9, 25.4, 25.8, 26.6, 34.6, and 35.3 ± 0.05° 2θ, preferably at least three, four, five, or all of the peaks. Particularly preferred is that the XRPD spectrum of crystalline form B has peaks at 25.4, 34.6, and 35.3 ± 0.1° 2θ, more preferably at 25.4, 34.6, and 35.3 ± 0.05° 2θ.

[0028] The tablet dosage form may contain crystalline form A, triethylenetetramine tetrahydrochloride. For example, the tablet dosage form may contain 60 to 95 wt% or 70 to 95 wt% of crystalline form A, triethylenetetramine tetrahydrochloride, preferably 70 to 90 wt%, more preferably 75 to 90 wt%, even more preferably 80 to 90 wt%, and still more preferably 80 to 85 wt% of crystalline form A, triethylenetetramine tetrahydrochloride. In one embodiment, the tablet dosage form contains crystalline form A, triethylenetetramine tetrahydrochloride, and does not contain crystalline form B, triethylenetetramine tetrahydrochloride.

[0029] The tablet dosage form may contain crystalline form B-triethylenetetramine tetrahydrochloride. For example, the tablet dosage form may contain 60 to 95 wt% or 70 to 95 wt% of crystalline form B-triethylenetetramine tetrahydrochloride, preferably 70 to 90 wt%, more preferably 75 to 90 wt%, even more preferably 80 to 90 wt%, and still more preferably 80 to 85 wt% of crystalline form B-triethylenetetramine tetrahydrochloride. In one embodiment, the tablet dosage form contains crystalline form B-triethylenetetramine tetrahydrochloride and does not contain crystalline form A-triethylenetetramine tetrahydrochloride.

[0030] The tablet dosage form may contain a mixture of crystalline form A and crystalline form B, triethylenetetramine tetrahydrochloride. For example, the tablet dosage form may contain 60 to 95 wt% or 70 to 95 wt% of a mixture of crystalline form A and crystalline form B, preferably 70 to 90 wt%, more preferably 75 to 90 wt%, even more preferably 80 to 90 wt%, and even more preferably 80 to 85 wt% of a mixture of crystalline form A and crystalline form B, triethylenetetramine tetrahydrochloride.

[0031] When a tablet dosage form comprises a mixture of crystalline form A and crystalline form B, triethylenetetramine tetrahydrochloride, the mixture may contain crystalline form A and crystalline form B in any relative amount. The mixture may contain no more than 50 wt% of crystalline form A, where wt% in this context refers to the weight expressed as the total amount of triethylenetetramine tetrahydrochloride in the tablet dosage form. Typically, the mixture contains no more than 40 wt% of crystalline form A, preferably no more than 30 wt% of crystalline form A, more preferably no more than 20 wt% of crystalline form A, and most preferably no more than 10 wt% of crystalline form A. In other words, the mixture typically contains at least 50 wt% of crystalline form B (where wt% in this context refers to the weight expressed as the total amount of triethylenetetramine tetrahydrochloride in the tablet dosage form), preferably at least 60 wt% of crystalline form B, more preferably at least 70 wt% of crystalline form B, even more preferably at least 80 wt% of crystalline form B, and most preferably at least 90 wt% of crystalline form B. However, in one embodiment, the mixture may contain at least 60 wt% of crystal form A, such as at least 70 wt%, at least 80 wt%, or at least 90 wt% of crystal form A. The mixture may contain no more than 40 wt% of crystal form B, such as no more than 30 wt%, no more than 20 wt%, or no more than 10 wt% of crystal form B.

[0032] The tablet dosage form includes a first lubricant. The first lubricant can be any lubricant suitable for the tablet dosage form, and such lubricants are known to those skilled in the art. The first lubricant may be selected from fatty acids or derivatives thereof, surfactants, inorganic materials, or polymers. The first lubricant may be selected from metal stearates or salts thereof (e.g., magnesium stearate, calcium stearate, zinc stearate, or sodium stearate fumarate), stearic acid, talc, magnesium aluminum silicate, sodium benzoate, poly(ethylene oxide) and poly(propylene oxide) copolymers (e.g., poloxamer 188), polyethylene glycol, sodium dodecyl sulfate, and vegetable oils. Preferably, the first lubricant is a metal stearate. More preferably, the metal stearate is one or more selected from magnesium stearate, calcium stearate, and zinc stearate. Most preferably, the metal stearate is magnesium stearate. Preferably, the first lubricant is not glyceryl dibehenate. Preferably, the first lubricant is not stearic acid. In some embodiments, the tablet dosage form does not contain stearic acid.

[0033] The tablet dosage form contains a first lubricant in an amount of 0.1 to 10 wt%. The tablet dosage form may contain a first lubricant in an amount of 0.1 to 8 wt%, for example, 0.1 to 5 wt%, or 0.1 to 4 wt%, or 0.1 to 3 wt%, or 0.1 to 2 wt%, or 0.1 to 1 wt%. Preferably, the tablet dosage form contains a first lubricant in an amount of less than 1 wt%, and more preferably less than 0.5 wt%. Preferably, the tablet dosage form contains a first lubricant in an amount of 0.1 to 0.5 wt% (e.g., 0.1 to 0.4 wt%), more preferably 0.1 to 0.3 wt%. Most preferably, the tablet dosage form contains a first lubricant in an amount of 0.15 to 0.25 wt%.

[0034] In some embodiments, the first lubricant is selected from talc and magnesium aluminum silicate, and the content of the first lubricant is 0.1 to 10 wt%, for example 0.1 to 8 wt%, or 0.1 to 5 wt%, or 0.1 to 3 wt%, or 0.1 to 2 wt%. In some embodiments, the first lubricant is selected from stearic acid, metal stearates, sodium benzoate, poly(ethylene oxide) and poly(propylene oxide) copolymers, polyethylene glycol, sodium dodecyl sulfate, and vegetable oils, and the content of the first lubricant is 0.1 to 5 wt%, for example 0.1 to 3 wt%, or 0.1 to 2 wt%, or 0.1 to 1 wt%. Preferably, the first lubricant is a metal stearate, and its content is 0.1 to 0.3 wt%. More preferably, the first lubricant is magnesium stearate, and its content is 0.1 to 0.3 wt%. The tablet may contain 0.7 to 2.0 mg of magnesium stearate, for example 1.0 to 1.5 mg of magnesium stearate.

[0035] Tablet dosage forms typically also contain one or more fillers. For example, a tablet dosage form may contain one, two, or three fillers. Preferably, the tablet dosage form contains one or two fillers, and more preferably one filler. The content of one or more fillers in the tablet may be 5 to 39.9 wt% or 5 to 29.9 wt% relative to the total weight of the tablet. Preferably, the content of one or more fillers in the tablet may be 5 to 25 wt% relative to the total weight of the tablet, more preferably 5 to 20 wt%, even more preferably 5 to 15 wt%, and even more preferably 9 to 15 wt%. Previously known tablet dosage forms typically contain more than 39.9 wt% filler because it was previously thought that a higher amount of filler was needed to provide the required component binding to prevent disintegration during tablet forming. However, it has been found that TETA 4HCl can be formulated into pharmaceutically acceptable tablets with a much lower filler dosage.

[0036] One or more fillers can be any suitable filler known in the art for preparing pharmaceutical formulations. Typically, one or more fillers comprise mannitol, lactose, cellulose, microcrystalline cellulose, calcium carbonate, sorbitol, and / or starch. Preferably, one or more fillers comprise mannitol, lactose, cellulose, microcrystalline cellulose, sorbitol, and / or starch. More preferably, one or more fillers comprise mannitol. In one embodiment, one or more fillers are mannitol. In some embodiments, the tablet dosage form comprises mannitol.

[0037] The tablet dosage form may contain one or more fillers in an amount of 5 to 39.9 wt% or 5 to 29.9 wt% relative to the total weight of the tablets, preferably 5 to 25 wt%, more preferably 5 to 20 wt%, even more preferably 5 to 15 wt%, and even more preferably 9 to 15 wt%, wherein one or more fillers include mannitol. Preferably, the tablet dosage form contains mannitol in an amount of 5 to 39.9 wt% or 5 to 29.9 wt% relative to the total weight of the tablets, preferably 5 to 25 wt%, more preferably 5 to 20 wt%, even more preferably 5 to 15 wt%, and even more preferably 9 to 15 wt%.

[0038] Preferred tablet dosage forms according to the present invention include:

[0039] A tablet dosage form comprising:

[0040] 70 to 95 wt% triethylenetetramine tetrahydrochloride; and

[0041] Metal stearates in a concentration of 0.1 to 0.3 wt%.

[0042] A tablet dosage form comprising:

[0043] 80 to 90 wt% triethylenetetramine tetrahydrochloride; and

[0044] Metal stearates in a concentration of 0.1 to 0.3 wt%.

[0045] A tablet dosage form comprising:

[0046] 80 to 85 wt% triethylenetetramine tetrahydrochloride; and

[0047] Metal stearates in a concentration of 0.1 to 0.3 wt%.

[0048] A tablet dosage form comprising:

[0049] 70 to 95 wt% triethylenetetramine tetrahydrochloride; and

[0050] Magnesium stearate in a content of 0.1 to 0.3 wt%.

[0051] A tablet dosage form comprising:

[0052] 80 to 90 wt% triethylenetetramine tetrahydrochloride; and

[0053] Magnesium stearate in a content of 0.1 to 0.3 wt%.

[0054] A tablet dosage form comprising:

[0055] 80 to 85 wt% triethylenetetramine tetrahydrochloride; and

[0056] Magnesium stearate in a content of 0.1 to 0.3 wt%.

[0057] A tablet dosage form comprising the following:

[0058] 70 to 95 wt% triethylenetetramine tetrahydrochloride;

[0059] 0.1 to 0.3 wt% magnesium stearate;

[0060] Mannitol, ranging from 5 to 29.9 wt%; and

[0061] 0 to 10 wt% of one or more other excipients,

[0062] The wt% amount is relative to the total weight of the tablets.

[0063] A tablet dosage form comprising the following:

[0064] 80 to 90 wt% of triethylenetetramine tetrahydrochloride;

[0065] 0.2 to 0.3 wt% magnesium stearate;

[0066] 5 to 15 wt% mannitol; and

[0067] 0 to 10 wt% of one or more other excipients,

[0068] The wt% amount is relative to the total weight of the tablets.

[0069] A tablet dosage form comprising the following:

[0070] 80 to 85 wt% of triethylenetetramine tetrahydrochloride;

[0071] 0.2 to 0.3 wt% magnesium stearate;

[0072] 9 to 15 wt% mannitol; and

[0073] 0 to 10 wt% of one or more other excipients,

[0074] The wt% amount is relative to the total weight of the tablets.

[0075] In addition to a first lubricant and optional one or more fillers, the tablet dosage form may also contain one or more excipients. Typically, the content of one or more other excipients is 0% to 10% of the total weight of the tablet. Preferably, the content of one or more other excipients is 2 to 9 wt% relative to the total weight of the tablet, more preferably 3 to 7 wt%.

[0076] In one embodiment, one or more excipients are selected from one or more stabilizers; one or more second lubricants (other than the first lubricant); and / or one or more coating excipients (preferably one or more film-coating excipients). Preferably, the tablet dosage form comprises one or more stabilizers and one or more second lubricants (other than the first lubricant). More preferably, the tablet dosage form comprises one or more stabilizers; one or more second lubricants (other than the first lubricant); and one or more film-coating excipients.

[0077] The tablet dosage form may contain one or more stabilizers in an amount of 0.1 to 0.5 wt% relative to the total weight of the tablets. Preferably, the tablet dosage form contains one or more stabilizers in an amount of 0.2 to 0.4 wt% relative to the total weight of the tablets.

[0078] One or more stabilizers can be any stabilizer suitable for tablet dosage forms, and such stabilizers are known to those skilled in the art. Suitable stabilizers include, for example, silica (preferably colloidal silica), syrup, gum arabic, gelatin, tragacanth gum, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and sucrose. Preferably, one or more stabilizers are selected from silica (preferably colloidal silica), polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and sucrose. In some embodiments, the tablet dosage form does not contain cellulose derivatives, such as methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropyl methylcellulose. In some embodiments, the tablet dosage form does not contain microcrystalline cellulose. More preferably, one or more stabilizers contain silica, most preferably colloidal silica. Preferably, one or more stabilizers are colloidal silica. The tablet dosage form preferably contains 0.1 to 0.5 wt%, more preferably 0.2 to 0.4 wt%, of colloidal silica relative to the total weight of the tablets.

[0079] The tablet dosage form may contain one or more second lubricants in a content of 0.5 to 2.5 wt% relative to the total weight of the tablets. Preferably, the tablet dosage form contains one or more second lubricants in a content of 1 to 2.5 wt% relative to the total weight of the tablets, more preferably 1 to 2 wt%.

[0080] One or more second lubricants can be any lubricant suitable for tablet formulations, and such lubricants are known to those skilled in the art. One or more second lubricants may be selected from the lubricants described herein as first lubricants. The first lubricant may be the same as or different from one or more second lubricants. Typically, the first lubricant differs from one or more second lubricants. Typically, one or more second lubricants comprise diglyceride behenate. Preferably, one or more second lubricants are diglyceride behenate. The tablet formulation preferably comprises diglyceride behenate. The tablet formulation preferably comprises diglyceride behenate in a content of 0.5 to 2.5 wt%, preferably 1 to 2.5 wt%, more preferably 1 to 2 wt% relative to the total weight of the tablets. Preferably, one or more second lubricants do not contain metal stearates, and more preferably do not contain magnesium stearate.

[0081] The tablet dosage form can be a coated tablet. Sugar coating or film coating can be used, with film coating being preferred. Coated tablets typically contain one or more coating excipients, typically one or more film coating excipients. The tablet dosage form may contain one or more coating excipients (preferably one or more film coating excipients) at a content of 0.1 to 7.5 wt% relative to the total weight of the tablets. Preferably, the tablet dosage form contains one or more coating excipients (preferably one or more film coating excipients) at a content of 0.5 to 7 wt%, more preferably 1 to 6 wt%, and more preferably 2 to 5 wt% relative to the total weight of the tablets.

[0082] One or more film-coating excipients can be any film-coating excipient suitable for forming coated tablets, and such film-coating excipients are known to those skilled in the art. Typically, one or more film-coating excipients are selected from cellulose derivatives (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and / or ethyl cellulose), vinyl derivatives (such as polyvinyl alcohol), alginates, polyols (such as polyethylene glycol and / or glycerol), acetate derivatives (such as glyceryl triacetate and / or triethyl citrate), glycerides, oils, colorants or pigments (such as titanium dioxide, iron oxide, natural colorants), and carbohydrates or sugars (such as lactose, lactose monohydrate, polydextrose, and / or starch). One or more film-coating excipients may comprise hydroxypropyl methylcellulose, lactose monohydrate, titanium dioxide, iron oxide, polyethylene glycol, and / or glyceryl triacetate. Preferably, one or more film-coating excipients comprise hydroxypropyl methylcellulose, lactose monohydrate, titanium dioxide, iron oxide, polyethylene glycol, and glyceryl triacetate.

[0083] Tablet dosage forms may contain other pharmaceutically acceptable excipients suitable for oral dosage forms, in addition to those specified above. These include, for example, carriers such as gelatin, sucrose, kaolin, dicalcium phosphate, and sodium chloride; disintegrants such as starch, alginate, alginate, or sodium starch glycolate; solubilizers such as cyclodextrin or modified cyclodextrin; effervescent mixtures; colorants; sweeteners; wetting agents such as lecithin, polysorbate alcohol, and lauryl sulfate; flavoring agents such as peppermint, wintergreen oil, and cherry flavoring; and, generally, non-toxic and pharmacologically inactive substances used in pharmaceutical preparations. Such pharmaceutical preparations can be manufactured in known ways, for example, by mixing.

[0084] In some embodiments, the tablet dosage form does not contain any pharmacologically active substance other than triethylenetetramine tetrahydrochloride. In other words, in some embodiments, the tablet dosage form contains triethylenetetramine tetrahydrochloride as the sole pharmacologically active substance. For example, it is preferred that the tablet dosage form does not contain a hypoglycemic agent. It is also preferred that the tablet dosage form does not contain an antihypertensive agent. More preferably, the tablet dosage form contains neither a hypoglycemic agent nor an antihypertensive agent. In some embodiments, the tablet dosage form contains only (i.e., consists of) triethylenetetramine tetrahydrochloride plus one or more excipients, wherein the excipients include at least a first lubricant. In this context, the term "excipient" refers to any substance that is not pharmacologically active (e.g., the various fillers, lubricants, stabilizers, and coatings described herein). In some embodiments, the tablet dosage form contains only (i.e., consists of) triethylenetetramine tetrahydrochloride and a first lubricant, and any one or more of the optional fillers, pharmaceutically acceptable excipients, and coatings described above.

[0085] In one embodiment, the tablet is a breakable tablet. The breakable tablet may have notches so that it can be easily broken by hand along the notches. The breakable tablet typically has a hardness of less than 370 N or less than 360 N, preferably less than 350 N, more preferably less than 340 N, even more preferably less than 330 N, further preferably less than 320 N, and most preferably less than 310 N. The tablet dosage form preferably has a hardness of at least 300 N, more preferably greater than 300 N. In one embodiment, the tablet has a hardness of 300 to 360 N, for example 300 to 350 N, preferably 300 to 340 N, more preferably 300 to 330 N, even more preferably 300 to 320 N, and most preferably 300 to 310 N. Hardness can be Ph.Eur. 10.0, 2.9.8 or USP (2024). <1217> The method of measurement is as follows. For example, hardness can be determined by measuring the force required to crush the tablet, where the hardness value is the average of 10 tablets. Specific conditions suitable for measuring hardness are described in more detail in Example 3.

[0086] The tablet's fragility is preferably less than 1%, for example, less than 0.75%, less than 0.5%, less than 0.25%, or less than 0.2%. Preferably, the tablet's fragility is less than 0.15%. Fragility can be specified using Ph.Eur. 10.0, 2.9.7, or USP (2024). <1216> The method of measurement is as follows. For example, crispness can be determined by tumbling uncoated tablets in a drum at a speed of 25 ± 1 rpm. Specific conditions suitable for measuring crispness are described in more detail in Example 3.

[0087] The tablet disintegration time is preferably less than 15 minutes, for example less than 10 minutes, less than 7 minutes, or less than 5 minutes. Preferably, the tablet disintegration time is less than 3 minutes. Disintegration time can be specified using Ph.Eur. 10.0, 2.9.1 or USP (2024). <701> The method for measuring disintegration time is as follows. For example, disintegration time can be recorded as the time required for 6 tablets to disintegrate in a liquid medium at 35-39°C. Specific conditions suitable for measuring disintegration time are described in more detail in Example 3.

[0088] The tablet dosage form may have a length L of 13 to 19 mm, a width W of 6 to 10 mm, and / or a height H of 4 to 7 mm. Preferably, the tablet dosage form has a length L of 14 to 18 mm, a width W of 7 to 9 mm, and / or a height H of 4.5 to 6.5 mm; more preferably, it has a length L of 15 to 17 mm, a width W of 7.5 to 8.5 mm, and / or a height H of 5 to 6 mm; most preferably, it has a length L of 15.5 to 16.5 mm, a width W of 7.5 to 8.5 mm, and / or a height H of 5 to 6 mm. Alternatively, the tablet dosage form may have a length L of 4 to 15 mm, a width W of 3 to 10 mm, and / or a height H of 2 to 7 mm. Preferably, the tablet dosage form has a length L of 5 to 12 mm, a width W of 4 to 9 mm, and / or a height H of 3 to 6 mm; more preferably, it has a length L of 5 to 10 mm, a width W of 5 to 9 mm, and / or a height H of 3 to 6 mm.

[0089] Tablet dosage forms can be of any suitable shape, such as round or elongated. Therefore, the maximum size of the tablet dosage form can be 13 to 19 mm, preferably 14 to 18 mm, more preferably 15 to 17 mm, and most preferably 15.5 to 16.5 mm. Alternatively, the maximum size of the tablet dosage form can be 4 to 15 mm, preferably 5 to 12 mm, more preferably 5 to 10 mm. In the case of round tablets, the maximum size is typically the diameter. In the case of elongated tablets, the maximum size is typically the length.

[0090] Preparation method of tablet dosage form

[0091] TETA.4HCl can be produced using techniques known in the art. For example, free TETA base is commercially available and can be converted to crystalline TETA hydrate and separated using conventional methods. TETA hydrate can be treated with an aqueous HCl solution to provide TETA.4HCl salt. Typically, TETA.40HCl salt is separated as a crude product and can be recrystallized as needed.

[0092] TETA.4HCl can be obtained in crystalline form, including polymorphs referred to as crystal form A and crystal form B. Recrystallization can be carried out using the techniques previously described. For example, crystalline TETA.4HCl can be obtained by antisolvent crystallization, typically by adding an antisolvent to an aqueous solution of TETA.4HCl and collecting the resulting crystals. Crystal form B TETA.4HCl can be obtained by recrystallization at a decreasing temperature of 15ºC or lower. A suitable method for obtaining TETA.4HCl is described in WO2019 / 211464.

[0093] TETA.4HCl can be ground or granulated before being formulated into tablets.

[0094] Tablet dosage forms can be prepared by mixing TETA.4HCl (optionally after grinding or granulation) with a core excipient (i.e., the excipient to be included in an uncoated tablet). Typically, the core excipient contains all the excipients to be included in the tablet dosage form except for the coating excipient, namely the first lubricant, optional filler, and optional one or more other excipients. TETA.4HCl and the core excipient can be compressed or molded into tablets. Compressed tablets can be prepared by mixing the active agent in free-flowing form (e.g., powder or granules) with the core excipient and then compressing it in a suitable machine. Molded tablets can be prepared by wetting a mixture of the powdered compound and the core excipient with an inert liquid diluent (e.g., purified water) and then molding it in a suitable machine.

[0095] In a preferred embodiment, the tablets are coated, for example by film coating or sugar coating, preferably by film coating.

[0096] In a preferred embodiment, the tablet has scoring. Preferably, the scoring tablet is a breakable tablet.

[0097] In one embodiment, the tablet is formulated to provide a slow or controlled release of the active agent.

[0098] In one embodiment, the tablet dosage form is produced by the following steps: (a) obtaining TETA.4HCl in pure crystalline form, for example using the method described above; (b) optionally grinding and / or granulating the obtained crystals; (c) mixing crystalline TETA.4HCl with a tablet core excipient; and (d) optionally mixing TETA.4HCl and the tablet core excipient; (e) pressing the mixture to form a tablet; and (f) optionally performing sugar coating or film coating.

[0099] Medical use

[0100] The therapeutically effective dose of the tablet formulation of this invention will be administered to the subject. It should be understood that the specific dose level for any particular subject will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, combination of medications, and the severity of the specific disease being treated. Optimal dose levels and dosing frequencies will generally be determined through clinical trials.

[0101] Typical daily doses are up to 25 mg of triethylenetetramine base per kg of body weight, for example, 0.001 to 25 mg of triethylenetetramine base per kg of body weight, preferably 5 to 25 mg of triethylenetetramine base per kg of body weight, depending on the age, weight, condition, type and severity of the disease, and frequency and route of administration of the subject to be treated. Preferably, the daily dose level is 150 mg to 1500 mg of triethylenetetramine (i.e., triethylenetetramine base), more preferably 300 mg to 1200 mg of triethylenetetramine base, and more preferably 450 to 975 mg of triethylenetetramine base. For pediatric use, the daily dose level is typically 150 mg to 600 mg of triethylenetetramine base. Triethylenetetramine is usually administered to patients in a non-toxic dose. Based on the relative molecular weights of triethylenetetramine and triethylenetetramine tetrahydrochloride, the corresponding dose level of triethylenetetramine tetrahydrochloride is approximately twice that of the active ingredient of triethylenetetramine.

[0102] The tablet formulations of the present invention can be administered to subjects once daily or multiple times daily (e.g., twice, three, or four times daily). The tablet formulations of the present invention are particularly suitable for once-daily administration to subjects. Therefore, in a preferred embodiment, the tablet formulation is administered to the subject once daily. When the tablet formulation is administered to the subject once daily, multiple tablet formulations can be administered together (e.g., one after another) to provide the required total daily dose.

[0103] This invention also provides a tablet dosage form as defined herein for a treatment method for treating a human or animal. Specifically, the tablet dosage form of this invention can be used to reduce copper levels in a subject and / or reduce the toxic effects of copper retention in the subject. Therefore, the tablet dosage form can be used to treat disorders and diseases associated with elevated copper levels. In particular, the tablet dosage form can be used to prevent or treat Wilson's disease. In one embodiment, the tablet dosage form can be used to treat Wilson's disease. In a preferred embodiment, the tablet dosage form can be used to treat a subject with Wilson's disease, wherein the tablet dosage form is administered to the subject once daily. In some embodiments, the tablet dosage form can be used to treat a subject with Wilson's disease who has not previously received treatment for Wilson's disease (also referred to as a previously untreated patient receiving first-line treatment). In some preferred embodiments, the tablet dosage form can be used to treat a subject with Wilson's disease who has not previously received treatment for Wilson's disease (i.e., a previously untreated subject), and wherein the tablet dosage form is administered to the subject once daily. In other embodiments, the tablet dosage form can be used to treat a subject with Wilson's disease who has previously received treatment for Wilson's disease with an active agent other than triethylenetetramine tetrahydrochloride (also known as second-line treatment). In some preferred embodiments, the tablet dosage form can be used to treat a subject with Wilson's disease who has previously received treatment for Wilson's disease with an active agent other than triethylenetetramine tetrahydrochloride, and the tablet dosage form is administered to the subject once daily. Such active agents are well known to those skilled in the art and include triethylenetetramine dihydrochloride, D-penicillamine, and zinc salts (such as zinc acetate).

[0104] The subjects treated according to the present invention can be human or animal subjects, particularly human or mammalian subjects, usually human.

[0105] This document also discloses a method for treating or preventing (preferably treating) Wilson's disease in a subject, the method comprising administering to the subject a tablet formulation as described herein. Preferably, the method comprises administering the tablet formulation once daily.

[0106] This document also discloses the use of triethylenetetraminetetrahydrochloride in the preparation of a medicament for the treatment or prevention (preferably treatment) of Wilson's disease in a subject, wherein the medicament is a tablet formulation as described herein. Preferably, the tablet formulation is administered to the subject once daily.

[0107] The tablet formulation of the present invention has optimal pharmacokinetic characteristics and, when administered to subjects, particularly when administered once daily, provides particularly optimized and effective serum AUC and C2. max and T max In one implementation, AUC 0-24(i.e., 0 to 24 hours after administration) is approximately 10,000 to 18,000 ng·hr / mL, for example, approximately 12,000 to 17,000 ng·hr / mL, or approximately 13,000 to 16,000 ng·hr / mL, or approximately 14,000 to 15,000 ng·hr / mL (when the daily dose is 900 mg tricentine, administered once daily). In one embodiment, the AUC 0-48 (i.e., 0 to 48 hours after administration) is approximately 10,000 to 19,000 ng·hr / mL, for example, approximately 12,000 to 18,000 ng·hr / mL, or approximately 14,000 to 17,000 ng·hr / mL, or approximately 15,000 to 16,000 ng·hr / mL (when the daily dose is 900 mg tricentine, administered once daily). In one embodiment, the invention provides an AUC after a single dose of the tablet formulation to the subject. 0-48 The AUC is the result of administering the same dose of Cuprio tablets twice daily (within a single day) to the subjects. 0-48 80-125%, for example, about 116%. In one embodiment, the C of the tablet dosage form of the present invention... max (When the daily dose is 900 mg trientamin, administered once daily) is about 2,500 to about 4,500 ng / mL, for example about 2,750 to about 4,250 ng / mL, or about 3,000 to about 4,000 ng / mL, or about 3,250 to about 4,000 ng / mL, or about 3,500 ng / mL to about 4,000 ng / mL. In one embodiment, the T of the tablet dosage form of the present invention... max (When the daily dose is 900 mg tricentine, administered once daily) the duration of action is approximately 0.5 hours to approximately 5 hours, for example, approximately 0.5 hours to approximately 4 hours, or approximately 0.5 hours to approximately 3 hours, or approximately 0.5 hours to approximately 2 hours, or approximately 0.5 hours to approximately 1.5 hours. It should be understood that when different doses are administered to subjects, the AUC, C... max and T max The values ​​will vary accordingly, but the values ​​above represent the physicochemical properties when administered at a once-daily dose of 900 mg tricentine. Alternative doses for administerable subjects are described in this article.

[0108] Specific aspects of the present invention are described below.

[0109] 1. A tablet dosage form comprising:

[0110] Triethylenetetramine tetrahydrochloride in a concentration of 60 to 95 wt%; and

[0111] A primary lubricant with a content of 0.1 to 10 wt%;

[0112] The wt% amount is based on the total weight of the tablets.

[0113] 2. The tablet dosage form according to aspect 1, comprising:

[0114] Triethylenetetramine tetrahydrochloride in a concentration of 70 to 95 wt%; and

[0115] A primary lubricant with a content of 0.1 to 10 wt%;

[0116] The wt% amount is based on the total weight of the tablets.

[0117] 3. The tablet dosage form according to aspect 1 or 2, comprising 80 to 95 wt% triethylenetetramine tetrahydrochloride.

[0118] 4. The tablet dosage form according to any of the foregoing aspects comprises 80 to 90 wt% triethylenetetramine tetrahydrochloride.

[0119] 5. The tablet dosage form according to any of the foregoing aspects comprises 80 to 85 wt% triethylenetetramine tetrahydrochloride.

[0120] 6. The tablet according to any of the foregoing aspects, wherein the triethylenetetramine tetrahydrochloride comprises not more than 50 wt% of crystal form A triethylenetetramine tetrahydrochloride and at least 50 wt% of crystal form B triethylenetetramine tetrahydrochloride, wherein the wt% refers to the weight expressed as the total amount of triethylenetetramine tetrahydrochloride in the tablet dosage form.

[0121] 7. The tablet dosage form according to any of the foregoing aspects comprises 70 to 95 wt%, preferably 80 to 95 wt%, more preferably 80 to 90 wt%, and even more preferably 80 to 85 wt% of crystalline form B triethylenetetramine tetrahydrochloride.

[0122] 8. The tablet dosage form according to any of the foregoing aspects, wherein the first lubricant is selected from fatty acids or derivatives thereof, surfactants, inorganic materials or polymers.

[0123] 9. The tablet dosage form according to any of the foregoing aspects, wherein the first lubricant is selected from talc and magnesium aluminum silicate.

[0124] 10. The tablet dosage form according to aspect 9, wherein the tablet dosage form comprises the first lubricant in an amount of 0.1 to 10 wt%.

[0125] 11. The tablet dosage form according to any one of aspects 1 to 8, wherein the first lubricant is selected from stearic acid, metal stearate, sodium benzoate, poly(ethylene oxide) and poly(propylene oxide) copolymers, polyethylene glycol, sodium dodecyl sulfate and vegetable oil.

[0126] 12. The tablet formulation according to aspect 11, wherein the tablet formulation comprises the first lubricant in an amount of 0.1 to 5 wt%.

[0127] 13. The tablet formulation according to any one of aspects 1 to 8, 11 or 12, wherein the first lubricant is a metal stearate.

[0128] 14. The tablet formulation according to aspect 13, wherein the tablet formulation comprises the first lubricant in an amount of 0.1 to 0.3 wt%.

[0129] 15. The tablet dosage form according to aspect 13 or aspect 14, wherein the metal stearate is one or more selected from magnesium stearate, calcium stearate and zinc stearate.

[0130] 16. The tablet formulation according to any one of aspects 13 to 15, wherein the first lubricant is magnesium stearate.

[0131] 17. The tablet dosage form according to aspect 16, comprising 0.7 to 2.0 mg of magnesium stearate.

[0132] 18. The tablet dosage form according to any of the foregoing aspects further comprises one or more fillers in a content of 5 to 39.9 wt% relative to the total weight of the tablets and one or more other excipients in a content of 0 to 10 wt% relative to the total weight of the tablets.

[0133] 19. The tablet dosage form according to aspect 18, wherein one or more fillers comprise mannitol, lactose, cellulose, microcrystalline cellulose, calcium carbonate, sorbitol and / or starch.

[0134] 20. The tablet dosage form according to aspect 18 or aspect 19, wherein one or more fillers comprise mannitol.

[0135] 21. The tablet dosage form according to any one of aspects 18 to 20, comprising 5 to 15 wt% of one or more fillers.

[0136] 22. The tablet dosage form according to aspect 21, comprising 9 to 15 wt% of one or more fillers.

[0137] 23. The tablet dosage form according to aspect 1, comprising the following:

[0138] 70 to 95 wt% triethylenetetramine tetrahydrochloride;

[0139] 0.1 to 0.3 wt% magnesium stearate;

[0140] 5% to 29.9% mannitol; and

[0141] 0 to 10 wt% of one or more other excipients,

[0142] The wt% amount is relative to the total weight of the tablets.

[0143] 24. The tablet dosage form according to aspect 1, comprising the following:

[0144] 80 to 90 wt% triethylenetetramine tetrahydrochloride;

[0145] 0.2 to 0.3 wt% magnesium stearate;

[0146] 5 to 15 wt% mannitol; and

[0147] 0 to 10 wt% of one or more other excipients,

[0148] The wt% amount is relative to the total weight of the tablets.

[0149] 25. The tablet dosage form according to aspect 1, comprising the following:

[0150] 80 to 85 wt% triethylenetetramine tetrahydrochloride;

[0151] 0.2 to 0.3 wt% magnesium stearate;

[0152] 9 to 15 wt% mannitol; and

[0153] 0 to 10 wt% of one or more other excipients,

[0154] The wt% amount is relative to the total weight of the tablets.

[0155] 26. The tablet dosage form according to any one of aspects 18 to 25, wherein the one or more other excipients are selected from one or more stabilizers; one or more second lubricants; and / or one or more film-coating excipients.

[0156] 27. The tablet dosage form according to aspect 26, wherein the tablet comprises 0.5 to 2.5 wt% of the one or more second lubricants relative to the total weight of the tablet.

[0157] 28. The tablet formulation according to any one of aspects 26 or 27, wherein the one or more second lubricants are disorbate diglycerides.

[0158] 29. The tablet dosage form according to any one of aspects 26 to 28, wherein the tablet comprises one or more stabilizers in an amount of 0.1 to 0.5 wt% relative to the total weight of the tablet.

[0159] 30. The tablet dosage form according to any one of aspects 26 to 29, wherein the one or more stabilizers are colloidal silica.

[0160] 31. The tablet dosage form according to any one of aspects 26 to 27, wherein the tablet is a coated tablet and comprises one or more film-coating excipients in an amount of 0.1 to 7.5 wt% relative to the total weight of the tablet.

[0161] 32. The tablet dosage form according to any of the foregoing aspects is a breakable tablet.

[0162] 33. The tablet dosage form according to any of the foregoing aspects, wherein the tablet has a hardness of 300 to 360 N.

[0163] 34. The tablet dosage form according to aspect 33, wherein the breakable tablet has a hardness of 300 to 310 N.

[0164] 35. The tablet dosage form according to any of the foregoing aspects, wherein the tablet has a brittleness of less than 0.15%.

[0165] 36. The tablet dosage form according to any of the foregoing aspects, wherein the tablet has a disintegration time of less than 5 minutes.

[0166] 37. The tablet dosage form according to any of the foregoing aspects, used for the prevention or treatment of Wilson's disease in the subject.

[0167] 38. The tablet dosage form for use according to aspect 37, wherein the dosage form is administered to the subject once daily.

[0168] The following examples illustrate the present invention, but are not intended to limit the scope of the invention.

[0169] Example

[0170] Reference Example 1: Known TETA 4HCl tablets

[0171] An example of a commercially available TETA 4HCl coated tablet is described in Table 1.

[0172] Table 1: Currently available commercially available TETA 4HCl coated tablets

[0173]

[0174] The average dimensions of the coated tablet core are L 16.2 mm x W 8.2 mm x H 4.9 mm.

[0175] Example 2: Preparation of tablets with high wt% active ingredients

[0176] A batch of 20 kg film-coated tablets was prepared according to the formulation in Table 2. All components were weighed according to the batch formulation and sieved using a vibrating sieve equipped with a stainless steel sieve with a 1 mm mesh size before feeding.

[0177] 16.99 kg of TETA 4HCl and 1.2 kg of mannitol were sieved and then mixed at 9 rpm for 10 minutes in a 300 L stainless steel hopper mixer (tumbler type). 0.06 kg of anhydrous colloidal silica and 1.38 kg of mannitol were sieved and added to the premix, then mixed at 9 rpm for another 10 minutes. 0.32 kg of disorbate glycerol and 0.04 kg of magnesium stearate were sieved and added to the mixture, and mixing was restarted at 9 rpm for 5 minutes until the final mixture was a smooth, white powder. The mixture was directly compressed into capsule-shaped tablet cores (approximately 16 × 8 mm) using a Fette 2090 rotary tablet press, with notches on both sides.

[0178] Prepare a 20% (w / w) suspension of Opadry® AMB II 88A120000 Yellow in purified water in a stainless steel container. The homogeneity of the film-coated suspension was visually inspected before use. Spray the film-coated suspension onto tablet cores in a perforated stainless steel coating pan (using inlet air temperature of 65°C and inlet air volume of 3.8 m³). 3 The calculated spray rate was 11 g / min. After the spraying process was completed, the film-coated tablets were removed from the film coating machine.

[0179] Table 2: Tablet Formulation of the Invention

[0180]

[0181] The average dimensions of the coated tablets are L 16.2 mm x W 8.2 mm x H 5.4 mm. An image of a representative tablet core is provided. Figure 1 middle.

[0182] This example demonstrates that tablet formulations containing significantly higher amounts of the active ingredient trientine (e.g., up to 95 wt% relative to the total weight of the tablet) than previously used can be prepared.

[0183] Example 3: Effect of magnesium stearate dosage in tablets

[0184] Additional tablet cores were prepared using the same process as in Example 2, but with different amounts of magnesium stearate, as shown in Table 3. The heights of tablet cores A and B were each 5.4 mm ± 0.1 mm. A film coating was then added according to the process described in Example 2.

[0185] Table 3: Tablets with different amounts of magnesium stearate

[0186]

[0187] The tablet cores (before film coating) were tested to evaluate their hardness, disintegration characteristics, and brittleness. The results are shown in Table 4.

[0188] Hardness was measured using the method described in Ph.Eur. 10.0, 2.9.8. For each composition, 10 tablets were tested, and the hardness value was the average hardness of the 10 tablets.

[0189] Disintegration time was measured using the method described in Ph.Eur. 10.0, 2.9.1. An apparatus is provided equipped with a basket assembly containing six test tubes movable in a liquid material. One tablet is placed in each test tube, and the liquid material is maintained at 35–39°C. The time required for all six tablets to disintegrate is measured. A tablet is considered disintegrated when no residue remains, or when any residue is a soft, hard, unwetted clump without a clearly perceptible core.

[0190] Brittleness was measured using the method described in Ph.Eur. 10.0, 2.9.7. Specifically, brittleness was measured using a drum with an inner diameter of 283–291 mm, a depth of 36–40 mm, made of a transparent synthetic polymer, and featuring a polished inner surface. The drum also included an arc-shaped protrusion. A sample of intact, uncoated tablets weighing 6.5 g was taken, dusted, weighed, and placed in the drum. The drum was rotated 100 times at 25 ± 1 rpm. The tablets were then removed, loose dust was removed, and the tablets were weighed again.

[0191] Table 4: Characteristics of tablet cores with different magnesium stearate contents

[0192]

[0193] in conclusion

[0194] Tablet cores formed with more than 80 wt% TETA 4HCl but without any magnesium stearate have a high hardness of 350 to 410 N (n=60). This high hardness means that the tablets are difficult to break by hand along the score lines. In contrast, tablets containing magnesium stearate have lower hardness, resulting in tablets that are easier to break (which may be important for achieving dosage adjustments).

[0195] The typical dosage of magnesium stearate in pharmaceutical formulations is 0.25–5 wt% (Shangraw et al., Pharm. Technol., 17(1) (1993) 32–44). Compared to tablet A (0 wt% magnesium stearate), the use of 0.2 wt% magnesium stearate had an unexpectedly significant effect on tablet hardness, given the extremely low amount of magnesium stearate present in Example 2. Further increasing the amount of magnesium stearate in tablet B (0.5 wt% magnesium stearate) did not provide any further significant benefit.

[0196] Furthermore, the tablet core of Example 2 (0.2 wt% magnesium stearate) exhibited a shorter disintegration time than tablet B (0.5 wt% magnesium stearate), which is beneficial for promoting the release of the active ingredient in pharmaceutical formulations. Therefore, this example demonstrates that the use of a low amount of 0.2 wt% magnesium stearate is unexpectedly associated with optimal hardness and disintegration characteristics.

[0197] Example 4: Comparison of once-daily dosing with the formulation of the present invention and twice-daily dosing with a known formulation

[0198] A randomized, open-label, two-way crossover study was conducted to evaluate and compare the pharmacokinetics, safety, and tolerability of a total daily dose of 900 mg TETA 4HCl administered once daily versus twice daily.

[0199] method

[0200] Twenty-six healthy subjects participated in the study. The crossover study included treatment phase 1 and treatment phase 2, each treatment phase consisting of a single dosing day, with a washout period of at least 5 days and up to 10 days between dosing days in each treatment phase. Figure 3 As shown.

[0201] During one treatment period, the subject received a single dose of 900 mg tricenttin (administered as 3 x 300 mg tablets according to Example 2). These tablets contained approximately 82 wt% TETA 4HCl (as a percentage of coated tablets) and had dimensions of approximately L 16.2 mm x W 8.2 mm x T 5.4 mm. During another treatment period, the subject received 450 mg tricenttin twice daily, 8 hours apart (administered as 3 x 150 mg Cuprior® tablets twice daily). The Cuprior® tablets contained approximately 48 wt% TETA 4HCl (as a percentage of coated tablets) and had dimensions of approximately L 16.2 mm x W 8.2 mm x T 4.9 mm.

[0202] For once-daily administration, serum samples were collected hourly for the first six hours after administration, followed by collection at 8, 12, 16, 20, 24, 36, and 48 hours. For twice-daily administration, serum samples were collected hourly for the first six hours after administration, hourly from the 8th hour after administration (concurrent with the second administration) until the 14th hour (i.e., six hours after the second administration), followed by collection at 16, 20, 24, 36, and 48 hours. Serum samples were used to determine the concentration of tricornidine in serum at each time point, as well as the concentrations of the two metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT).

[0203] result

[0204] No significant adverse events were observed in either group of the study. The results are shown in Tables 5 to 8.

[0205] Table 5: Results of Bioavailability Study

[0206]

[0207] T administered twice daily max The value represents the T value of the first dose in a two-dose series. max .

[0208]

[0209]

[0210]

[0211] in conclusion

[0212] Surprisingly, once-daily dosing with the formulation of this invention has been found to provide higher tricenttin bioavailability than twice-daily dosing with the known Cuprio tablets, as evidenced by the higher AUC (24hr), (48hr), and (unlimited) values ​​for once-daily dosing. Specifically, the AUC (48hr) for once-daily dosing is 116% of the AUC (48hr) for twice-daily dosing. This higher bioavailability is particularly advantageous because it allows for a reduction in the amount of tricenttin required in a given subject to achieve the same therapeutic effect, thereby further reducing the medication burden and improving treatment adherence to a greater extent. Although C maxThe total exposure (AUC) was higher than with the known twice-daily administration of Cuprio tablets, but no safety issues were observed with once-daily administration, a finding that is particularly valuable. Furthermore, the results in Tables 7 and 8 indicate that the key metabolites MAT and DAT were cleared from the body in similar manner after both once-daily and twice-daily administration.

Claims

1. A tablet dosage form comprising: Triethylenetetramine tetrahydrochloride in a concentration of 60 to 95 wt%; and A primary lubricant with a content of 0.1 to 10 wt%; The wt% amount is relative to the total weight of the tablets.

2. The tablet formulation according to claim 1, comprising 70 to 95 wt% of triethylenetetramine tetrahydrochloride, preferably comprising 80 to 95 wt% of triethylenetetramine tetrahydrochloride, more preferably 80 to 90 wt% of triethylenetetramine tetrahydrochloride, and even more preferably 80 to 85 wt% of triethylenetetramine tetrahydrochloride.

3. The tablet formulation according to claim 1 or claim 2, wherein the triethylenetetramine tetrahydrochloride comprises not more than 50 wt% of crystal form A triethylenetetramine tetrahydrochloride and at least 50 wt% of crystal form B triethylenetetramine tetrahydrochloride, wherein wt% refers to the weight expressed as the total amount of triethylenetetramine tetrahydrochloride in the tablet formulation.

4. The tablet dosage form according to any one of the preceding claims, comprising 70 to 95 wt%, preferably 80 to 95 wt%, more preferably 80 to 90 wt%, and even more preferably 80 to 85 wt% of crystalline form B triethylenetetramine tetrahydrochloride.

5. The tablet dosage form according to any one of the preceding claims, wherein the first lubricant is selected from fatty acids or derivatives thereof, surfactants, inorganic materials or polymers.

6. The tablet dosage form according to any one of the preceding claims, wherein: (a) The first lubricant is selected from talc and magnesium aluminum silicate, optionally wherein the tablet dosage form comprises 0.1 to 10 wt% of the first lubricant; or (b) The first lubricant is selected from stearic acid, metal stearates, sodium benzoate, poly(ethylene oxide) and poly(propylene oxide) copolymers, polyethylene glycol, sodium dodecyl sulfate and vegetable oils, and optionally the tablet dosage form comprises 0.1 to 5 wt% of the first lubricant.

7. The tablet dosage form according to any one of claims 1 to 6, wherein the first lubricant is a metal stearate; optionally wherein (a) The metal stearate is one or more selected from magnesium stearate, calcium stearate, and zinc stearate; and further optionally, the metal stearate is magnesium stearate; and / or (b) The tablet formulation contains 0.1 to 0.3 wt% of the first lubricant.

8. The tablet formulation according to any one of claims 1 to 6, wherein the first lubricant is magnesium stearate, and wherein the tablet formulation comprises 0.7 to 2.0 mg of magnesium stearate.

9. The tablet dosage form according to any one of the preceding claims further comprises one or more fillers in an amount of 5 to 39.9 wt%, optionally 5 to 29.9 wt%, relative to the total weight of the tablets, and one or more other excipients in an amount of 0 to 10 wt%, relative to the total weight of the tablets.

10. The tablet dosage form of claim 9, wherein the one or more fillers comprise mannitol, lactose, cellulose, microcrystalline cellulose, calcium carbonate, sorbitol and / or starch, optionally wherein the one or more fillers comprise mannitol.

11. The tablet dosage form according to claim 9 or claim 10, comprising 5 to 15 wt% of one or more fillers, optionally 9 to 15 wt% of one or more fillers.

12. The tablet dosage form according to claim 1, comprising the following: (a) 70 to 95 wt% triethylenetetramine tetrahydrochloride; 0.1 to 0.3 wt% magnesium stearate; 5 to 29.9 wt% mannitol; and 0 to 10 wt% of one or more other excipients, The wt% amount is relative to the total weight of the tablets; or (b) 80 to 90 wt% triethylenetetramine tetrahydrochloride; 0.2 to 0.3 wt% magnesium stearate; 5 to 15 wt% mannitol; and 0 to 10 wt% of one or more other excipients, The wt% amount is relative to the total weight of the tablets; or (c) 80 to 85 wt% triethylenetetramine tetrahydrochloride; 0.2 to 0.3 wt% magnesium stearate; 9 to 15 wt% mannitol; and 0 to 10 wt% of one or more other excipients, The wt% amount is relative to the total weight of the tablets.

13. The tablet dosage form according to any one of claims 9 to 12, wherein the one or more other excipients are selected from one or more stabilizers; one or more second lubricants; and / or one or more film-coating excipients; optionally wherein the one or more second lubricants are glyceryl disorbate and / or the one or more stabilizers are colloidal silica.

14. The tablet dosage form of claim 13, wherein the tablet comprises one or more of the second lubricants in an amount of 0.5 to 2.5 wt% relative to the total weight of the tablets; and / or the tablet comprises one or more of the stabilizers in an amount of 0.1 to 0.5 wt% relative to the total weight of the tablets; and / or the tablet is a coated tablet and comprises one or more film-coating excipients in an amount of 0.1 to 7.5 wt% relative to the total weight of the tablets.

15. The tablet dosage form according to any one of the preceding claims, wherein: (a) The tablet is a breakable tablet; and / or (b) The tablet has a hardness of 300 to 360 N, optionally 300 to 310 N; and / or (c) The tablet has a brittleness of less than 0.15%; and / or (d) The tablet has a disintegration time of less than 5 minutes.

16. A tablet dosage form according to any one of the preceding claims, for the prevention or treatment of Wilson's disease in a subject, optionally wherein the dosage form is administered to the subject once daily.

Images