WO2023173185A1

WO2023173185A1 - Liquid solution of tadalafil, bioequivalent to its form of reference (tablet), and formulation for pharmaceutical product of liquid solution of tadalafil, bioequivalent to the tablet form

Info

Publication number: WO2023173185A1
Application number: PCT/BR2022/050219
Authority: WO
Inventors: Luis Pereira
Original assignee: Luis Pereira
Priority date: 2022-03-16
Filing date: 2022-06-14
Publication date: 2023-09-21

Abstract

The invention relates to a liquid solution of tadalafil which is bioequivalent to the original Cialis tablet, in a liquid, soluble and mucoadhesive form, packaged in a spray bottle for oral and sublingual use. Tadalafil obtained in this way is used by spraying into the oral and sublingual regions, the amount sprayed being adjustable by the patient to the desired dose, 2.5 mg of tadalafil being released with each spray. The dose can be adjusted between 2.5 and 20 mg (which are the Cialis doses, i.e. 2.5, 5, 10 and 20 mg) at the request of the doctor or the wish of the patient, depending on age and the degree and type of problem to be treated. The solubilisation reached, which is more than 20,000 times the original solubilisation of Cialis, with gradual absorption without modifying the bioavailability of the reference tablet (Cialis), allows treatment of prostatic hyperplasia, erectile dysfunction or pulmonary hypertension etc., in an unprecedented manner in relation to the pharmaceutical forms already known. The formulation can be produced without the active substance tadalafil at first, in order to receive the tadalafil mixture as a liquid solution in a separate step, maintaining the same principles of bioequivalence to Cialis, with solubility, mucoadhesion and the mode of application.

Description

“LIQUID TADALAFIL SOLUTION, BIOEQUIVALENT TO ITS REFERENCE FORM (TABLET), AND FORMULATION FOR PHARMACEUTICAL PRODUCT IN LIQUID TADALAFIL SOLUTION, BIOEQUIVALENT TO TABLET FORM”

[001] This descriptive report refers to the invention patent application for a pharmaceutical product in the form of a liquid, homogeneous and mucoadhesive solution of Tadalafil, which is proven to be bioequivalent to the 10mg Cialis® tablet, packaged in Buccal Spray for the treatment of Erectile Dysfunction. It is, therefore, a liquid solution of Tadalafil, bioequivalent to Cialis, used via Buccal Spray.

Prior art comments

[002] Cialis is a safe medicine, a world reference, with numerous therapeutic advantages in relation to a longer half-life than its competitors. There is scientific evidence and clinical studies widely recognized worldwide by the medical and scientific community regarding its effectiveness and safety. It is only manufactured in solid tablet pharmaceutical form and is therefore administered orally.

[003] The tablet brings a series of limitations not related to the drug itself, but precisely because of its pharmaceutical form, that is, the solid state, per tablet, to be swallowed.

[004] Because it is solid, health problems related to this pharmaceutical form and its route of administration have been observed, such as cases of dysphagia, dyspepsia and gastrointestinal problems. Difficulties in swallowing the tablet are also common in the population (around 10%), as is the occurrence of allergic reactions to the excipients and dyes present in this tablet. Furthermore, due to the impossibility of dividing doses homogeneously, any possible dose adjustments are hampered as the tablets cannot and should not be broken or crushed.

[005] Liquid medication solutions or suspensions, in turn, can now be divided and have better digestion, but they do not have the same pharmacokinetics as tablets, thus altering bioavailability. The liquid behaves completely differently from the solid when absorbed by the body and this changes the pharmacokinetic characteristics of the medicines when their pharmaceutical form is changed. If pharmacokinetics are substantially altered, as occurs with changes in pharmaceutical forms, the medicines cannot be considered as bioequivalent, precisely because these physical changes end up altering their absorption curve and pharmacokinetic profile.

[006] Therefore, the medicine needs to be studied again, to check whether changes in pharmacokinetics have not impaired its efficacy and safety.

[007] It is not known that a liquid form of Tadalafil, in solution or suspension, is proven to be bioequivalent to the solid form of the Cialis tablet.

[008] Tadalafil is extremely insoluble and its transformation into liquid, without proper technology and care, would completely alter its pharmacokinetics in relation to the reference tablet, in this case Cialis 10mg.

[009] Another problem with tablets is the chemical excipients present, which in the case of Cialis, are, among others, yellow iron oxide, triacetin and titanium dioxide. These excipients are potentially toxic and used outside the pharmaceutical industry as in the tobacco industry and others.

[010] Tadalafil is offered to the market in liquid form, as shown, for example, in patent document WO 2017069533, entitled “ORAL LIQUID FORMULATION OF TADALAFIL”, where an oral liquid formulation contains Tadalafil or a pharmaceutically acceptable salt thereof, as active ingredient. A type of composition proposed in this document is shown in the table below:

Tadalafil 10mg

Transcutol®HP 1800mg

Cremophor® EL 200mg 200mg

Purified water Appropriate volume

Total volume 3,000mg

011] In this prior art composition, shown by document WO 2017069533, Transcutol® HP was added with Cremophor® EL and completely dissolved with stirring, after which Tadalafil was added and completely dissolved. After mixing was complete, purified water was added, mixed well and stirred slowly. After adding the mixture of purified and homogenized water, more purified water was added until a constant volume was reached for this oral liquid formulation of Tadalafil.

[012] The method and composition mentioned above, as well as others, attempt to improve the state of the art of the pharmaceutical form by making it soluble, but do not offer the condition of bioequivalence to the reference tablet, which is the object of this application.

[013] The ideal situation for an evolution in relation to the state of the art, mainly for the pharmaceutical market, would be the possibility of administering a liquid product, bioequivalent to Cialis.

Purpose of the order

[014] It is precisely the proof of bioequivalence, achieved through a formulation, between these different pharmaceutical forms, that is the proposal for this patent application, called TADALAFIL LIQUID SOLUTION BIOEQUIVALENT TO ITS REFERENCE FORM (TABLET), AND FORMULATION FOR PHARMACEUTICAL PRODUCT IN TADALAFIL LIQUID SOLUTION, BIOQUIVALENT TO TABLET FORM”.

[015] Such a condition is made possible, therefore, through this pharmaceutical formulation developed from solid Tadalafil, which was transformed into a liquid and mucoadhesive solution, with agitation and temperature that made the Tadalafil solution bioequivalent to the reference tablet, Cialis .

[016] Thus, in liquid, soluble form and with mucoadhesive properties, the formulated solution can be used through atomizers in mouth spray pumps, with a specific spray valve.

[017] This form of liquid Tadalafil, bioequivalent to the solid form of Cialis, due to its originality (unprecedented until then), comes to annul all the problems related to the conventional tablet, completely transforming it into its form and offering it to the market, in fact, as a “liquid Cialis”.

[018] In this way, all its benefits, such as efficacy and safety, already recognized, remain present, but in a new pharmaceutical form with its advantages of fractionation, digestion and [019] fewer adverse effects.

[020] The proposed formulation, packaged in a spray bottle, releases homogeneously, 2.5 mg of Tadalafil per jet, which can be adjusted by the patient or doctor to the desired dose, between 2.5 and 20mg (which are the doses of Cialis, between 2.5, 5, 10 and 20mg) . If side effects occur due to dosage, the medication can be reduced (thus avoiding splitting tablets) and if the desired effect does not occur, it can be increased.

[021] Therefore, patients who are treated with Cialis®, prescribed by their doctors, if they are not adapting to the use of said pill due to the previously mentioned undesirable effects or others, have solved their problems through the liquid therapeutic solution of Tadalafil.

[022] To this end, the formulation contains a technological combination of solubilization and mucoadhesion that together allow, at the same time, to dissolve the medicine and make it remain in the mucous membranes through the bioadhesion mechanism, without the risk of changes in bioavailability.

[023] The state of the art already includes liquid Tadalafil, whether in suspension or solution, as well as the solvents, diluents and excipients used, have existed for years.

[024] The inventive activity, which created a new and unpredictable situation, was precisely the exact mixing of several already existing components in a specific route of administration, sublingual and oral, at appropriate temperature and pressure, with Tadalafil, to solve the problem. problem (already described) existing in the prior art, relating to the Cialis® tablet.

[025] When creating a liquid product, bioequivalent to a hitherto insoluble and solid medicine, a unique inventive activity is detected, with the numerous advantages already listed and without any additional risk. [026] An important change in pharmacokinetics would be expected, due to the change in physical state, but the invention achieved was the change in the state without changes in pharmacokinetics, thus allowing the use of bioequivalence.

[027] Thus, the mixture of solvents with mucoadhesive agents in certain specific conditions of use, evolved the state of the art, bringing a new and unpredictable result today applied to Tadalafil.

[028] The inventive activity was, therefore, not to create a new medicine with a better effect, with more effect or power of action, nor to solubilize or bioadhesive it, but rather to create a liquid medicine that behaves in the human body as if it were solid, with the mmeessmmaass pharmacokinetic characteristics of the reference tablet, Cialis.

[029] This pharmacokinetic mimicry of liquid Tadalafil, behaving like a solid tablet in terms of pharmacokinetic absorption, is an inventive and unprecedented activity in science.

[030] Thus, we have the "fingerprint" of Cialis' bioequivalence, printed on this Tadalafil Liquid Solution. The pharmacokinetic reference parameters (AUC and Cmax), brought by the scientific study that was sponsored by the author of this patent application, prove this statement.

[031] Bioequivalence allows the safe, reliable and scientifically proven use of an already known medicine, in this case Cialis, but which until then did not have a liquid version, according to the existing state of the art.

[032] "A caveat here is to the rule of combining documents to prove the existence of inventive activity, which occurs when the combination of existing techniques brings, new and unpredictable technician. A very illustrative example of this type of situation is the invention of gunpowder, which consists of a combination of saltpeter, sulfur and coal. The three aforementioned elements were already well known at the time of the creation of gunpowder and their individual properties and particularities were known to all those who had contact with such elements." httDs://oconsultorempatentes.com/atividade-inventiva/.

[033] Next, returning to the matter, results from the BLCL-TAD-PK01 study, contracted by the author of this patent application, are presented, with the aim of proving the results of its formulation. [034] The BLCL-TAD-PK01 study was a single-center, single-dose, open-label, laboratory-blind, randomized, four-sequence, four-sequence scientific study (References [10 mg], Test 1 [5 mg], Test 2 [10 mg], Test 3 [15 mg]), four-period crossover studies in fasted healthy male volunteers.

[035] The test product was administered at a concentration of Tadalafil 2.5 mg by metered dose sublingual spray. The test doses were 2 sprays (5mg), 4 sprays (10mg) and 6 sprays (15mg).

[036] The reference product (Cialis®) was a 10 mg oral film-coated tablet, produced by Lilly’s of the Netherlands.

[037] The doses of the experimental products were separated by an elimination interval of at least 7 calendar days.

[038] Sixteen (16) healthy individuals were enrolled. Fourteen (14) subjects have evaluable pharmacokinetic data for the baseline period and at least one from the test period. These individuals constitute the pharmacokinetic analysis population.

[039] A summary of the pharmacokinetic parameters observed is the assessment of bioequivalence for the parameters of interest Cmax (maximum concentration of the active ingredient and the time required to reach this concentration), AUCO-t (area on the blood concentration curve versus time in which the active ingredient), and AUCO-oo, are presented below. Individual plasma concentration-time profiles are also presented. The analysis was performed in Phoenix® WinNonlin®, version 8.1.

[040] A test dose is considered bioequivalent to the reference dose if the test GMR for reference and the 90% CI for Cmax and AUC0-t when are within the acceptance range of 80.00 - 125.00%.

[041] The results for each test comparison, for reference, are presented below:

Test 1 [5 mg] versus Reference [10 mg]:

- Cmax: 52.15% (46.04 - 59.07)

- AUC0-t: 50.65% (44.40 - 57.79);

Test 2 [10 mg] versus Reference [10 mg]:

- Cmax: 88.0% (79.05 - 97.95)

- AUC0-t: 97.89% (89.57 - 106.97);

Test 3 [15 mg] versus Reference [10 mg]:

- Cmax: 103.95% (92.96 - 116.23)

- AUC0-t: 121.32% (109.23 - 134.75).

Tadalafil Cmax and AUCO-oo increased in a dose-dependent manner after administration as a sublingual spray.

[042] The above study proved the bioequivalence of 4 spray jets of Tadalafil (10mg) with 10mg Cialis.

[043] The final result was a solution absorbed gradually and gradually without important changes in pharmacokinetics, thus maintaining bioequivalence in relation to the reference tablet (Cialis 10mg), with the advantages and practicalities of the form liquid. This will help patients who need Cialis and doctors who need to prescribe it but encounter difficulties inherent in solid dosage forms.

[044] Bioadhesiveness means that the formulation is not lost due to the "wash out" effect, which is the "washing" that occurs through the action of saliva and protects the molecules of gastric juices. In other words, the liquid "sticks" to the mucous membranes of the mouth and gastrointestinal tract and is gradually released, protected from this “washing” by gastric chemical attacks. This way, patients can be treated for the same diseases in which Cialis is used, such as prostate hyperplasia, erectile dysfunction or pulmonary hypertension (Adcirca®). The treatment dosage depends on the patient's age, type and degree of the problem, and can be adjusted more easily. Due to this possibility of adjusting doses, the patient can use the right amount for each type of problem, obviously, at medical discretion.

[045] Digestion and absorption in the gastrointestinal tract is easier, without causing problems, as the medicine is already in a liquid solution. This convenience of use is especially welcome in elderly patients, diabetics, those with neurological conditions or gastric problems. These patients are more likely to have problems with gastric emptying and, consequently, with digestion and absorption of tablets.

Claims

1 - “LIQUID SOLUTION OF TADALAFIL, BIOEQUIVALENT TO ITS REFERENCE FORM (TABLET)”, where a liquid formulation, in a homogeneous solution of Tadalafil, for oral or sublingual use, is characterized by bioequivalence to the Cialis tablet of 2.5, 5, 10 or 20mg, based on the pharmacokinetic parameters Cmax, AUC and GMean.

2 - “LIQUID TADALAFIL SOLUTION, BIOEQUIVALENT TO ITS REFERENCE FORM (TABLET)”, where a liquid formulation, for oral or sublingual use, in a homogeneous Tadalafil solution of 20mg/ml to release 2.5mg of active ingredient per feather jet or other (flow of 0.125ml per pump), is characterized by bioequivalence to the Cialis tablet, in dosages of 2.5mg to 20mg (1 to 8 buccal jets).

3 - “FORMULATION FOR PHARMACEUTICAL PRODUCT IN TADALAFIL LIQUID SOLUTION, BIOEQUIVALENT TO TABLET FORM”, where the liquid solution of claims 1 and 2 is obtained from a formulation of Tadalafil in a volume of water and/or with a mixture of components that contains a solvent such as Ethanol or PEG (Polyethylene glycol), associated or not with a mucoadhesive or emulsifying agent, such as Kollifor RH 40 (Polioxyl), Povidone or other, such components being homogenized for fine dispersion of particles in order to dilute the solid (IPDE) in the liquid, in a process carried out in high-frequency mixing equipment at approximately between 1 and 50,000 rpm (preferably 26,000), at a temperature between 20 and 300°C (approximately 80), pressurized between 0 and 10 bar (preferably 1 bar), passed through an industrial barrier filter 10 microns (or similar) and resting between 10 minutes and 3 hours (preferably 2h) to reach pH 66 to 8 (preferably 7); being a solution packaged in an aerosol spray bottle for dosing, which initially "sticks" to the mucous membranes of the mouth and gastrointestinal tract for gradual release, said solution characterized by reaching the absorption curve considered bioequivalent to the Cialis tablet, through the Cmax parameters, between 80 to 125% and bioequivalence GMean.

4 - “FORMULATION FOR PHARMACEUTICAL PRODUCT IN LIQUID TADALAFIL SOLUTION, BIOEQUIVALENT TO TABLET FORM”, according to claim 3, characterized by the absorption curve, using a 5mg Cialis tablet, between 46.04 - 59.07% (Cmax) and between 44.40

- 57.79% (AUCO-t).

5 - “FORMULATION FOR PHARMACEUTICAL PRODUCT IN LIQUID TADALAFIL SOLUTION, BIOEQUIVALENT TO TABLET FORM”, according to claim 3, characterized by the absorption curve, using a 10mg Cialis tablet, between 79.05 - 97.95% (Cmax) and between 89.57

- 106.97 (AUC0-t).

6 - “FORMULATION FOR PHARMACEUTICAL PRODUCT IN LIQUID TADALAFIL SOLUTION, BIOEQUIVALENT TO TABLET FORM”, according to claim 3, characterized by the absorption curve, using a 15mg Cialis tablet, between 92.96 - 116.23% (Cmax) and 109.23 - 134.75 (AUC0-t).

7 - “FORMULATION FOR PHARMACEUTICAL PRODUCT”, according to any of the previous claims, the formulation characterized in that, optionally, it is produced without the active ingredient Tadalafil to receive, in a separate step, the mixture and homogenization of Tadalafil, making it liquid, soluble, mucoadhesive and bioequivalent to Cialis.