Analgesic dosage form for oral administration with abuse-deterrent properties

Abstract

The invention relates to a solid, analgesic dosage form for oral administration with abuse deterrent properties, said dosage form comprising: (a) one or more active ingredients having potential for abuse selected from the group consisting of Alfentanil, Benzhydrocodone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Fentanyl, Hydrocodone, hydrocodone bitartrate, Hydromorphone, Levorphanol tartrate, Meperidine hydrochloride, Methadone, Morphine, Normethadone, Opium, Oxycodone, Oxymorphone, Pentazocine, Tapentadol, Tramadol, TEV-90105, ELI-202, or pharmaceutically acceptable salts and solvates thereof; (b) magnesium salt selected from the group consisting of consisting of Magnesium acetate, Magnesium benzoate, Magnesium bromate, Magnesium bromide, Magnesium carbonate, Magnesium chlorate, Magnesium chloride, Magnesium chromate, Magnesium citrate, Magnesium fluoride, Magnesium fluorosilicate, Magnesium formate, Magnesium glycinate, magnesium hydroaspartate, Magnesium hydroxide, Magnesium iodate, Magnesium iodide, Magnesium lactate, Magnesium L-threonate, Magnesium Malate, Magnesium molybdate, Magnesium nitrate, Magnesium oxalate, Magnesium oxide, Magnesium perchlorate, Magnesium phosphate, Magnesium selenite, Magnesium sulfate, Magnesium sulfate heptahydrate, Magnesium sulfite, Magnesium thiosulfate or a combination thereof, c) piperine.

Description

Provisional Patent ApplicationApplicants: Orphinic sp z o.o.ASLAB Science Prosta Spotka AkcyjnaInventors: >Title: Analgesic Dosage Form for Oral Administration with Abuse-deterrent PropertiesBACKGROUND OF THE INVENTION1. Field of the Invention

[0001] The subject of the present invention relates to a new solid, analgesic dosage form for oral administration with abuse-deterrent properties.

[0002] The present invention relates to the field of opioid drugs and drug abuse.

[0003] The present invention relates to a solid dosage form with reduced parenteral abuse containing, in addition to one or more active ingredients with potential for abuse.

[0004] Opioid analgesics have been the mainstay for the treatment of pain for centuries, starting from opium poppy cultivation to modem opioid therapies and synthetic opioids. Either way, all opioids are chemically related and interact with opioid receptors on nerve cells in the body and brain.

[0005] Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Furthermore, regular opioid use can lead to dependence, and when misused, opioid drugs can lead to addiction, overdose incidents, and even death. Thus, literature indicates that opioids should be prescribed at the lowest dose possible to provide adequate analgesia for improvement in the quality of the patient’s life and for improvement in function (Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid complications and side effects. Pain Physician. 2008 Mar; 11 (2 Suppl):S105-20).

[0006] Some methods are therefore dedicated to increasing the efficiency of lower dosages. For instance, document EP2714042 A1 relates to a pharmaceutical composition for use in oral treatment of pain comprising an opioid with the addition of magnesium saltthat increases the availability of the drug. Said composition comprises an opioid and a pharmaceutically admissible salt of magnesium (II) selected from a group consisting of: magnesium lactate, magnesium hydroaspartate or magnesium citrate, wherein the magnesium (II) salt is in finely particulated form of D90 < 50 pm in size. Wherein said opioid is preferably selected from a group consisting of: morphine, codeine, dihydrocodeine, oxycodone, Tramadol or their pharmaceutically admissible salts.

[0007] Many pharmaceutical active ingredients, in addition to having excellent activity in their appropriate application, also have potential for abuse, i.e. , they can be used by an abuser to bring about effects other than those intended. Opiates, for example, which are highly active in combating severe to very severe pain, are frequently used by abusers to induce a state of narcosis or euphoria.

[0008] Dosage forms that contain active ingredients with potential for abuse, even when taken orally in an abusively large quantity, do not usually give rise to the result desired by the abuser, namely a rapid rush or “kick,” because blood levels of the active ingredients increase only slowly. In order nevertheless to achieve the desired effects and enable abuse, the corresponding dosage forms are comminuted, for example, ground, by the abuser, and the active ingredient is extracted from the powder obtained by comminution of the dosage form with the assistance of a preferably aqueous liquid, preferably the minimum quantity necessary, and the resultant solution, optionally after filtration through cotton wool or cellulose wadding, is administered parenterally, in particular intravenously. Due to this parenteral administration, only the smallest possible quantities of an aqueous liquid are used for extraction, in particular, so as to obtain the smallest possible injection volume with an active ingredient, which results in the desired rapid rush or “kick.” In this manner, parenteral administration, in comparison with oral administration, tends to give rise to an accelerated rise in levels of the active ingredient, providing the abuser with the desired result.

[0009] Nevertheless, the abuse of opioid drugs has become a serious and growing public health concern. According to U.S. Food and Drug Administration (FDA) abusedeterrent formulations are defined as formulations that target the known or expected routes of abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid drug substance (https: / / www.fda.gov / drugs / postmarket-drug-safetyinformation-patients-and-providers / abuse-deterrent-opioid-analgesics. Accessed March 23, 2020).

[0010] Moreover, FDA guidelines (U.S. Food and Drug Administration: Abuse deterrent opioids — evaluation and labeling. Guidance for industry. 2015. Available at: https: / / www.fda.gov / regulatory-information / search-fda-guidance-documents / abuse deterrent-opioids-evaluation-and-labeling. Accessed March 23, 2020) distinguishes seven possible general categories of abuse-deterrent strategies:

[0011] 1. Physical / chemical barriers that provide resistance to mechanical alteration or limit the change of physical form of an opioid drug. In this context, chemical barriers (like gelling agents or solvents) can resist extraction of the opioid from the dosage form, and physical barriers prevent chewing, crushing, cutting, or grinding of the dosage form.

[0012] Regarding chemical barriers, US10130586 document relates to a controlled release oral solid dosage form comprising a first population of particles comprising an opioid analgesic and a second population of particles comprising a gelling agent. Wherein said opioid particles are free from gelling agent and said gelling agent is free from said opioid particles. However, when said dosage form is exposed to from about 0.5 ml to about 10 ml of water, the dosage form forms a gel that cannot be drawn into an insulin syringe without picking up pockets of air.

[0013] Regarding physical barriers, document US10130591 reveals an abuse deterrent dosage form with increased breaking strength of the tablets.

[0014] A similar approach is presented in US9943513 relating to an oxycodone dosage which is resistant to crushing, grating, grinding, cutting, solvation, or dissolution in water or alcohol. Said dosage comprises a capsule encapsulating about 35% to about 70% by mass glyceryl monolinoleate; about 20% to about 50% by mass polyethylene oxide comprising having a molecular weight (Mv) of about 1 ,000,000 to about 7,000,000; and about 1 % to about 20% by mass of oxycodone or a salt thereof. The dosage was heated to about 50° C to about 80° C for about 10 min to about 180 min and cooled to room temperature.

[0015] 2. Agonist / antagonist combination - this technology relates to combined dosage forms that comprise addition of agonist / antagonist, which reduce or suppress theeuphoria associated with abuse. Wherein said agonist / antagonist is released only upon manipulation of the product.

[0016] 3. Aversion - this strategy relates to adding aversive substances that produce an unpleasant effect if a dosage form is manipulated (e.g., nasal irritant) or is used at a higher dosage than directed.

[0017] 4. Delivery systems - this strategy relates to either new or unconventional opioid delivery systems implants that are difficult to manipulate. Sustained-release depot injectable formulations or subcutaneous implants are good examples of this strategy.

[0018] 5. New molecular prodrugs or new molecular entities that include a need for enzymatic activation, different receptor binding profiles, central nervous system penetration or chemical transformations in order to release the active ingredients of the opioid.

[0019] 6. The combination approach relates to a combination of two or more methods, including the above methods.

[0020] 7. Novel approaches or new technologies not characterized in previous categories.

[0021] However, Litman and co-workers indicate that only the first three of these deterrent methods currently exist in the marketplace (Ronald S. Litman, Olivia H. Pagan, Theodore J. Cicero; Abuse-deterrent Opioid Formulations. Anesthesiology 2018; 128(5): 1015-1026. doi: https: / / doi.Org / 10.1097 / ALN.0000000000002031 .).BRIEF SUMMARY OF THE INVENTION

[0022] The aim of this invention is to provide a new analgesic dosage form for oral administration with abuse-deterrent properties to limit the risk of abuse that follows the sixth approach, i.e. the combination approach.

[0023] Unexpectedly, this goal has been achieved by the present invention. The subject of the present invention is a solid, analgesic dosage form for oral administration with abuse-deterrent properties; said dosage form comprising: one or more active ingredients having potential for abuse selected from the group consisting of Alfentanil, Benzhydrocodone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Fentanyl, Hydrocodone, hydrocodone bitartrate, Hydromorphone, Levorphanol tartrate, Meperidinehydrochloride, Methadone, Morphine, Normethadone, Opium, Oxycodone, Oxymorphone, Pentazocine, Tapentadol, Tramadol, TEV-90105, ELI-202 and pharmaceutically acceptable salts and solvates thereof;

[0025] The magnesium salt selected from the group consisting of Magnesium acetate, Magnesium benzoate, Magnesium bromate, Magnesium bromide, Magnesium carbonate, Magnesium chlorate, Magnesium chloride, Magnesium chromate, Magnesium citrate, Magnesium fluoride, Magnesium fluorosilicate, Magnesium formate, Magnesium glycinate, magnesium hydroaspartate, Magnesium hydroxide, Magnesium iodate, Magnesium iodide, Magnesium lactate, Magnesium L-threonate, Magnesium Malate, Magnesium molybdate, Magnesium nitrate, Magnesium oxalate, Magnesium oxide, Magnesium perchlorate, Magnesium phosphate, Magnesium selenite, Magnesium selenite, Magnesium sulfate, Magnesium sulfate heptahydrate, Magnesium sulfite, Magnesium thiosulfate or a combination thereof,

[0026] A piperine, an alkaloid in a form of extract from piper nigrum and piper longum or a synthetically produced substance.

[0027] Preferably, said dosage administered through nasal mucosa produces an unpleasant local sensation and discourages abuse.

[0028] Preferably, said dosage administered through intravenous injection increases osmolarity and / or alters pH of the extract, therefore producing pain and irritation at the injection site and discouraging abuse.

[0029] Preferably, said dosage comprises a mass ratio of active ingredient to magnesium salt ranging from 0.1 :1 to 4: 1 .

[0030] Preferably, said dosage comprises a mass ratio of active ingredient to magnesium salt to piperine ranging from 0.15 :1 to 4:1 to 0.01 :1.

[0031] Preferably, said dosage comprises a mass ratio of active ingredient to magnesium salt equivalent to regulatory approved strength of active ingredient divided by the mass of magnesium salt containing 75 mg to 100 mg of elemental magnesium (Table 1):Table 1. Examples of dosage compositions:

[0032] Preferably, one or more active ingredients that have the potential for abuse comprise less than 20% and preferably less than 10% of the composition by mass.

[0033] Preferably, magnesium salt comprises 50-80% of the composition by mass.

[0034] Preferably the dosage is compressed in a tablet.

[0035] Preferably, said dosage has an osmolarity 544 to 606 mOsm / L.

[0036] Preferably, said dosage has a pH ranging from 6.3 to 6.64.

[0037] Preferably, said dosage exceeded the hardness threshold of 150 N.

[0038] Preferably, said dosage has hardness ranging from 192 to 279 N.BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Fig. 1 shows a calibration curve for the determination of tramadol content HPLC with UV-VIS Detection.

[0040] Fig. 2 shows particle size distribution for Trabumag samples after mortar grinding.

[0041] Fig. 3 shows particle size distribution for Trabumag samples after grinding with a mill.

[0042] Fig. 4 shows particle size distribution for Tramadol HCI (3 tablets) after mortar grinding.

[0043] Fig. 5 shows particle size distribution for Tramadol HCI (3 tablets) after grinding with a mill.DETAILED DESCRIPTION OF THE INVENTION

[0044] In one embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet. Nevertheless, the opioid analgesic formulation, according to the invention, can be formulated as an immediate- release formulation or controlled-release oral formulation in any suitable tablet, coated tablet or multi particulate formulation known to those skilled in the art.

[0045] In certain embodiments, opioids used in the composition according to the present invention are selected from Alfentanil, Benzhydrocodone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Fentanyl, Hydrocodone, hydrocodone bitartrate, Hydromorphone, Levorphanol tartrate, Meperidine hydrochloride, Methadone, Morphine, Normethadone, Opium, Oxycodone, Oxymorphone, Pentazocine, Tapentadol, Tramadol, TEV-90105, ELI-202, or and pharmaceutically acceptable salts and solvates.

[0046] In certain embodiments magnesium salts are selected from the group consisting of Magnesium acetate, Magnesium benzoate, Magnesium bromate, Magnesium bromide, Magnesium carbonate, Magnesium chlorate, Magnesium chloride, Magnesium chromate, Magnesium citrate, Magnesium fluoride, Magnesium fluorosilicate, Magnesium formate, Magnesium glycinate, magnesium hydroaspartate, Magnesium hydroxide, Magnesium iodate, Magnesium iodide, Magnesium lactate, Magnesium L threonate, Magnesium Malate, Magnesium molybdate, Magnesium nitrate, Magnesium oxalate, Magnesium oxide, Magnesium perchlorate, Magnesium phosphate, Magnesium selenite, Magnesium selenite, Magnesium sulfate, Magnesium sulfate heptahydrate, Magnesium sulfite, Magnesium thiosulfate or their combinations.

[0047] In certain embodiments, piperine is used as a supplementary abuse deterrent.

[0048] In certain embodiments, examples of excipients necessary for the manufacturing of an orally administered composition according to the invention include:

[0049] one or more fillers such as dibasic calcium phosphate, lactose, starches, dextrose, sorbitol, microcrystalline cellulose, or any other pharmaceutically acceptablefiller known in the art;

[0050] one or more lubricants such as polyethylene glycol, magnesium stearate, stearic acid, sodium stearyl fumarate, sodium behenate, or any other pharmaceutically acceptable lubricant known in the art;

[0051] one or more binders such as cellulose, methylcellulose, polyvinyl pyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose, talc, stearic acid, magnesium stearate, calcium stearate, polyethylene glycol, or any other pharmaceutically acceptable binder known in the art;

[0052] one or more glidants such as: fumed silica, talc, magnesium carbonate, colloidal silicon dioxide (Carbosil), com starch, or any other pharmaceutically acceptable glidant known in the art.

[0053] One or more dyes such as titanium dioxide, brilliant blue, indigo carmine, amaranth carmine, saffron, caramel, tetrazine, or any other dye known in the art;

[0054] one or more flavoring and sweetening agents such as clove oil, citric and syrup, glycerin, rose oil, orange oil, menthol, sucrose, saccharin, aspartame, sorbitol, sucralose; or any other flavoring known in the art;

[0055] one or more surfactants such as sodium lauryl sulfate, cetyl trimethyl ammonium bromide, polyoxyethylene sorbitol monooleate), Lecithin; or any other pharmaceutically acceptable surfactant known in the art;

[0056] one or more disintegrants, such as: Polyvinyl pyrrolidone, carboxymethyl cellulose, and sodium starch glycolate, croscarmellose sodium, starches, cross-linked polymers, modified starches such as primogel and Explotab (TM), Veegum (TM) HV, or any other pharmaceutically acceptable disintegrant known in the art;

[0057] one or more preservatives, such as: methyl paraben, ethyl paraben, propyl paraben, benzoic acid and its salts, sorbic acid, and its salts, or any other pharmaceutically acceptable preservative known in the art.

[0058] In certain embodiments, the composition according to invention is compressed to a tablet.

[0059] In certain embodiments, said tablet comprising composition according to invention has an osmolarity 544 to 606 mOsm / L.

[0560] In certain embodiments, said tablet comprising composition according toinvention has a pH ranging from 6.3 to 6.64.

[0061] In certain embodiments, said tablet comprising composition according to invention exceeded the hardness threshold of 150 N.

[0062] In preferable embodiments, the hardness of said tablet ranges from 192 to 279 N.

[0063] The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.

[0064] Example 1

[0065] In one embodiment described herein, a dosage form of the invention comprises an abuse-deterrent pharmaceutical composition in the form of a compressed tablet, wherein the active ingredient having potential for abuse is oxycodone. The composition of said tablet is presented in Table 2.Table 2. Exemplary composition of oxycodone tablet according to the invention

[0066] In this non-limiting example, oxycodone represents an exemplary compound that can be exchanged by any compound selected from the group consistingof: Alfentanil, Benzhydrocodone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Fentanyl, Hydrocodone, hydrocodone bitartrate, Hydromorphone, Levorphanol tartrate, Meperidine hydrochloride, Methadone, Morphine, Normethadone, Opium, Oxycodone, Oxymorphone, Pentazocine, Tapentadol, Tramadol, TEV-90105, ELI-202 and pharmaceutically acceptable salts and solvates thereof.

[0067] In this non-limiting example, Magnesium Lactate dihydrate was used, however any magnesium salt selected from the group consisting of Magnesium acetate, Magnesium benzoate, Magnesium bromate, Magnesium bromide, Magnesium carbonate, Magnesium chlorate, Magnesium chloride, Magnesium chromate, Magnesium citrate, Magnesium fluoride, Magnesium fluorosilicate, Magnesium formate, Magnesium glycinate, magnesium hydro aspartate, Magnesium hydroxide, Magnesium iodate, Magnesium iodide, Magnesium lactate, Magnesium L-threonate, Magnesium Malate, Magnesium molybdate, Magnesium nitrate, Magnesium oxalate, Magnesium oxide, Magnesium perchlorate, Magnesium phosphate, Magnesium selenite, Magnesium selenite, Magnesium sulfate, Magnesium sulfate heptahydrate, Magnesium sulfite, Magnesium thiosulfate or their combinations, can be used in the composition according to the invention.

[0068] The matrix tablets were produced in the following manner in a batch size of 1000 tablets using a process described herein.

[0069] Example 2

[0070] In one embodiment described herein, a dosage form of the invention comprises an abuse-deterrent pharmaceutical composition in the form of a compressed tablet, wherein the active ingredient having potential for abuse is oxycodone. The composition of said tablet is presented in Table 3.Table 3. Exemplary composition of oxycodone tablet with piperine according to the invention

[0071] In this non-limiting example, oxycodone represents an exemplary compound that can be exchanged by any compound selected from the group consisting of: Alfentanil, Benzhydrocodone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Fentanyl, Hydrocodone, hydrocodone bitartrate, Hydromorphone, Levorphanol tartrate, Meperidine hydrochloride, Methadone, Morphine, Normethadone, Opium, Oxycodone, Oxymorphone, Pentazocine, Tapentadol, Tramadol, TEV-90105, ELI-202 and pharmaceutically acceptable salts and solvates thereof.

[0072] In this non-limiting example, Magnesium Lactate dihydrate was used, however any magnesium salt selected from the group consisting of Magnesium acetate, Magnesium benzoate, Magnesium bromate, Magnesium bromide, Magnesium carbonate, Magnesium chlorate, Magnesium chloride, Magnesium chromate, Magnesium citrate, Magnesium fluoride, Magnesium fluorosilicate, Magnesium formate, Magnesium glycinate, magnesium hydro aspartate, Magnesium hydroxide, Magnesium iodate, Magnesium iodide, Magnesium lactate, Magnesium L-threonate, Magnesium Malate, Magnesium molybdate, Magnesium nitrate, Magnesium oxalate, Magnesium oxide, Magnesium perchlorate, Magnesium phosphate, Magnesium selenite, Magnesium selenite, Magnesium sulfate, Magnesium sulfate heptahydrate, Magnesium sulfite, Magnesium thiosulfate or their combinations, can be used in the composition according to the invention.

[0073] In this non-limiting example, piperine was used,

[0074] The matrix tablets were produced in the following manner in a batch size of 1000 tablets using a process described herein.

[0075] Example 3

[0076] Another embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet comprising Tramadol as an active ingredient having the potential for abuse. The Composition of said tablet is presented in Table 4.Table 4. Exemplary composition of Tramadol tablet according to the invention

[0077] The matrix tablets were produced in the following manner in a batch size of 1000 tablets, a description is provided herein.

[0078] Example 4.

[0079] Another embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet comprising fentanyl as an active ingredient having the potential for abuse.

[0080] The Composition of said tablet is presented in Table 5.Table 5. Exemplary composition of Fentanyl tablet according to the invention

[0081] Example 5.

[0082] Another embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet comprising methadone as an active ingredient having the potential for abuse. The composition of said tablet is presented in Table 6.Table 6. Exemplary composition of methadone tablet according to the invention

[0083] Example 6.

[0084] Another embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet comprising codeine as an active ingredient having the potential for abuse. The composition of the said tablet is presented in Table 7.Table 7. Exemplary composition of codeine tablet according to the invention

[0085] Example 7

[0086] Another embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet comprising hydrocodone as an active ingredient having the potential for abuse. The composition of said tablet is presented in Table 8.Table 8. Exemplary composition of hydrocodone according to theinvention

[0087] Example 8

[0088] Another embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet comprising hydromorphone as an active ingredient having the potential for abuse. The composition of said tablet is presented in Table 9.Table 9. Exemplary composition of hydromorphone according to the invention

[0089] Example 9

[0090] Another embodiment described herein is an oral abuse-deterrent pharmaceutical composition in the form of a compressed tablet comprising Tramadol as an active ingredient having the potential for abuse. The composition of said tablet is presented in Table 10.Table 10. Exemplary composition of Tramadol according to the invention

[0091] Example 10

[0092] Intranasal route abuse-deterrent properties of the pharmaceutical composition described in Example 1 will be based on lower content of active opioid substance per mass unit as compared with reference extended release formulation. Table below illustrates relative content of Active Pharmacutical Substance (Oxycodone HCI) in a pharmaceutical composition described in Example 1 and in reference extended-releasecapsules (Banner Life Sciences). Results are shown in table 11 .

[0093] Table 11 . Comparison of intranasal route abuse-deterrent properties

[0094] After pulverization of the pharmaceutical composition described in Example 1 , the resulting mass of powder for nasal administration will contain 2.14 % weight of oxycodone HCI, which is 5-fold lower than the content of oxycodone in pulverized a reference extended-release composition. Inhalation of a similar amount of powder from pulverized tablet of Example 1 will produce much lesser, if an, narcotic or euphoric effect. In addition, presence of magnesium salt in the powder will cause irritation of the nasal mucosa and unpleasant sensation, with a discouraging effect on the abuser.

[0095] Example 11.

[0096] Phase I Study - Abuse Potential Assessment of Intranasally Administered Pharmaceutical Composition Described in Example 1 Compared To Oxycodone HCI Extended-Release And PlaceboQualitative composition of the reference preparation (Oxycontin 20 mg):Oxycodone hydrochloride 20 mg active substanceButylated Hydroxytoluene (BHT) Stabilizer, protection against oxidationHypromellose Sustained release matrixPEG 400 Facilitates dissolution and release of the drugMagnesium stearate Anti-caking agentTitanium dioxide Coating dyePolysorbate 80 Emulsifier, supporting coatingFerric oxide red Pink dye

[0097] This is a single-dose, randomized, double-blind, placebo-controlled, three- way crossover study designed to evaluate the relative abuse potential of crushed Pharmaceutical Composition Described in Example 1 compared to Oxycodone HCI Extended Release and placebo in healthy male and female, non-dependent, recreational opioid users.

[0098] Study Design:Enrollment: 33 participantsAllocation: RandomizedIntervention Model: Crossover Assignment Masking: Double (Participant, Investigator)

[0103] Placebo Comparator: Treatment A Lactose (900 mg) placebo tablets crushed; single dose

[0104] Experimental: Treatment B Pharmaceutical Composition Described in Example 2; capsule contents crushed; single dose

[0105] Active Comparator: Treatment COxycodone HCI Extended Release 20 mg crushed

[0106] Primary Outcome MeasureDrug Liking Visual Analog Scale maximum peak effect (Emax);Drug Liking Visual Analog Scale Area under the effect curve to 24 hours (AUE0- 24h);High Visual Analog Scale maximum peak effect (Emax);High Visual Analog Scale Area under the effect curve to 24 hours (AUE0-24h).

[0107] Secondary Outcome Measures:Good Drug Effects Visual Analog Scale maximum peak effect Bad Drug Effects Visual Analog Scale maximum peak effect Feel Sick Visual Analog Scale maximum peak effect Nausea Visual Analog Scale maximum peak effect Sleepy Visual Analog Scale maximum peak effectDizzy Visual Analog Scale maximum peak effectPupil Diameter minimum peak effect (Emin)Take Drug Again Visual Analog Scale maximum peak effect Subject Rating Scale - Need to Blow Nose maximum peak effect Subject Rating Scale - Runny Nose / Nasal Discharge maximum peak effect Subject Rating Scale - Burning maximum peak effectSubject Rating Scale - Facial Pain / Pressure maximum peak effect Subject Rating Scale - Nasal Congestion maximum peak effect Plasma oxycodone - Maximum observed plasma concentration (Cmax) Plasma oxycodone - Time to maximum observed plasma concentration (Tmax) Plasma oxycodone - Area under the plasma concentration time curve from time zero to 24 hour (AUC0-24h)Plasma noroxycodone - Maximum observed plasma concentration (Cmax) Plasma noroxycodone - Time to maximum observed plasma concentration (Tmax) Plasma noroxycodone - Area under the plasma concentration time curve from time zero to 24 hour (AUC0-24h)

[0099] Criteria:

[0100] Inclusion Criteria:Healthy male or female subjects 18 to 55 years of age, inclusive.The subject is a recreational opioid user who is NOT dependent on opioids based on Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition Text Revision (DSM-IV-TR) criteria and the Naloxone Challenge. A recreational opioid user is defined as use of opioids for non-therapeutic purposes (i.e. , for psychoactive effects) on at least 10 occasions within the last year and at least once in the 12 weeks before the Screening Visit.Subjects must have experience with intranasal drug administration, defined as intranasal use on at least 3 occasions within the last year prior to the Screening Visit.

[0101] Exclusion Criteria:Diagnosis of substance and / or alcohol dependence (excluding caffeine and nicotine), as assessed by the Investigator using the DSM IV-TR criteria. Has participated in, is currently participating in, or is seeking treatment for substance- and or alcohol- related disorders (excluding nicotine and caffeine). Has any condition in which an opioid is contraindicated, e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, or is suspected of having paralytic ileus.Allergy or history of hypersensitivity to morphine sulfate, other opioids, naltrexone hydrochloride, naloxone, and / or lactose.History or current clinically significant neurological, cardiovascular, renal, hepatic, endocrine, gastrointestinal, hematologic, or metabolic disease as evaluated by the Investigator.History or current pulmonary disease including asthma, chronic obstructive pulmonary disease, exercise-induced asthma, bronchitis, and obstructive sleep apnea.

[0102] Example 12

[0103] A comparative evaluation between two pharmaceutical formulations containing 50 mg of Tramadol Hydrochloride (Tramadol HCI): a standard formulation and an Abuse-Deterrent Formulation (ADF) according to invention referred to as Trabumag.Trabumag (according to SmPC):* the actual quantity is calculated based on assay and loss on drying values in particular batches of tramadol hydrochloride and magnesium lactate dihydrate, micronised, compensated with a suitable amount of microcrystalline cellulose.**removed in the drying processTested tablet Tramadol HCI:Tablet weight: 200 mg% weightTramadol HCI 25 50Solutab A 5 10Microcell 102 69 138Magnesium stearate 1 2

[0104] Visual descriptionTrabumag Tablet: The tablet is white, rectangular and biconvex, with a powdery texture to the touch and a compact structure.Tramadol HCI Tablet: The tablet is white, round and biconvex, with a smooth surface and a compact structure. It has a central groove, no visible coatings and presents a solid and uniform appearance upon visual inspection.

[0105] The oblong shape of the study tablet (Trabumag) may provide added value over the round tablet (Tramadol HCI), primarily in the context of designing an abusedeterrent dosage form (ADF). Literature and experience indicate that:• Oblong tablets are more difficult to crush evenly, especially using improvised tools (e.g., spoons or cards).• Oblong tablets with rounded ends are more difficult to grip and mechanically process, which may reduce the likelihood of manipulation.• From an ADF design perspective, the unusual shape may also complicate tablet insertion into the decompression equipment used for parenteral abuse (e.g., grinders, mechanical pestles).

[0106] Therefore, the shape of the Trabumag tablet should be considered a supporting element for its abuse-deterrent properties.

[0107] Weight measurements

[0108] The tablet weight measurements for both Trabumag and Tramadol HCI were performed using a RADWAG precision balance, Model: AS 220. 2 PLUS, which provides high-accuracy weighing with readability up to 0.1 mg. The evaluation of individual tablet weights is a critical parameter in compliance with pharmacopoeial standards, as it ensures uniformity of dosage units, confirming consistency in the amount of active pharmaceutical ingredient (API) delivered per tablet.

[0109] From an Abuse-Deterrent Formulation (ADF) perspective, accurate weight determination also allows for the assessment of tampering potential, especially when tablets are manipulated for extraction or dose escalation. Variations in weight may indicate irregular compression or formulation inconsistencies, which could affect mechanical resistance, solubility, and extraction behavior, key factors in ADF design. Therefore, weight measurement plays a dual role in both regulatory compliance and risk assessment for abuse deterrence.

[0110] Table 12. Weight comparison of Trabumag and Tramadol HCI

[0111] The weight analysis of the Trabumag tablets resulted in a standard deviation (SD) of 12.09 mg and a relative standard deviation (RSD) of 1.3%, while the Tramadol HCI tablets showed a SD of 1 .78 mg and RSD of 0.87%.

[0112] According to pharmacopoeial guidelines (e.g., USP <905> and Ph. Eur. 2.9.5), RSD values below 2% are generally considered acceptable for tablet weight uniformity, especially when tablets are within a typical weight range. Therefore, both products meet the required criteria, indicating good manufacturing consistency.

[0113] Volume and density

[0114] The volume of individual tablets of Trabumag and Tramadol HCI was determined using the Archimedes displacement method, in accordance with basic physicochemical principles. Each tablet was carefully weighed using a precision analytical balance (previously described: RADWAG Model AS 220. R2 PLUS), and its volume was measured by displacement in a graduated 10 mL cylinder filled partially with deionized water. Results were shown in Table 13.

[0115] To ensure accuracy:1 . An initial water volume (Vi) was recorded.2. The tablet was gently submerged in the water without trapping air bubbles.3. The new water level (V2) was measured.

[0116] The volume of the tablet was calculated as:Volume (mL) = V2-V1Once the mass (m) in miligrams (mg) and the volume (V) in mililiters (mL) were known, the density (mg / mL) was calculated using the formula:Density (mg / mL) = Masa (mg) / Volume (mL)

[0117] Table 13. Volume and density of Trabumag and Tramadol HCI

[0118] Higher density increases tablet hardness and complicates crushing. In turn, a larger tablet volume affects the ratio of opioid to total tablet weight, making this ratio unfavorable from an abuse perspective. The same dose of opioid is contained in severaltimes the mass of ingredients. Recreational abuse would require crushing and administering, for example, intranasally, five times more crushed tablet in powder form than a control tablet of typical market weight.

[0119] Hardness

[0120] The determination of tablet hardness is a fundamental physical test in the quality control of solid oral dosage forms. According to the United States Pharmacopeia (USP <1217>) and the European Pharmacopoeia (Ph. Eur. 2.9.8), this test assesses the mechanical strength of a tablet against pressure or compression, which is essential to ensure its integrity during packaging, transport, and handling.

[0121] Beyond logistical considerations, tablet hardness can also impact critical quality attributes such as disintegration time and drug release profile, particularly in immediate-release formulations.

[0122] A tablet that is too friable may break or crumble before administration, while one that is excessively hard may hinder adequate disintegration and reduce bioavailability.

[0123] For these reasons, the pharmacopeias recognize hardness testing as a complementary evaluation to disintegration and dissolution testing, and consider it an essential tool to ensure the pharmaceutical quality and consistency of solid oral products.

[0124] The hardness of tramadol tablets was evaluated using the ERWEKA TBH 125 hardness tester, a specialized device for the physical quality control of solid oral dosage forms. A total of 10 tablets of each type (e.g., different batches or formulations) were analyzed, in accordance with the guidelines of the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Eur.).

[0125] The TBH 125 measures the force required to break a tablet by applying axial pressure, with results typically expressed in Newtons (N). This value reflects the mechanical resistance of the tablet, a critical parameter that impacts both handling and transport, as well as the release of the active pharmaceutical ingredient. Results are presented in Table 14.

[0126] Table 14. Hardness of Trabumag and Tramadol HCI

[0127] As presented in Table 14, the ADF formulation of Trabumag exceeded the hardness threshold of 150 N established by the United States Pharmacopeia (USP) for abuse-deterrent formulations. These values fall within the expected range for ADF products, contributing to a physical barrier against tampering and misuse. In contrast, the standard Tramadol HCI formulation also demonstrated appropriate hardness values. As it is not designed as an ADF, its hardness falls within the 30-100 N range, which is consistent with the requirements for immediate oral disintegration. These results indicate that both formulations exhibit physical characteristics suitable for their intended therapeutic purposes.

[0128] Size of grain crushed in kitchen mortar and grinding in a coffee grinder

[0129] Particle size measurement is a critical parameter in the development, quality control, and therapeutic performance of both solid and liquid pharmaceutical dosage forms. As outlined by official pharmacopeias such as the United States Pharmacopeia (USP <429>) and the European Pharmacopoeia (Ph. Eur. 2.9.31 ), particle size directly influences key aspects of a pharmaceutical product, including dissolution rate, bioavailability, physical and chemical stability, and content uniformity.

[0130] In particular, for drugs with low solubility or modified-release formulations,precise particle size control is essential to ensure an appropriate pharmacokinetic profile. Likewise, in suspensions and dispersed systems, maintaining a uniform particle size distribution is crucial to prevent issues such as sedimentation, aggregation, or dosing variability.

[0131] Pharmacopeias recommend validated analytical techniques such as laser diffraction, optical microscopy, or sieving, depending on the nature of the material and the required size range. These methods must meet stringent criteria for accuracy, reproducibility, and traceability, and are integral to the regulatory submission and final product specifications.

[0132] To measure the particle size in Trabumag and Tramadol HCI, a SALD-2300 laser diffraction particle size analyzer (Shimadzu) was employed. This instrument is widely recognized for its accuracy and broad measurement range (17 nm to 2500 pm), making it particularly suitable for complex biological matrices.

[0133] The selection of this method is based on the guidelines established by various pharmacopeias, including the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Eur.), both of which recognize laser diffraction as a validated and standardized technique for determining particle size distribution in liquid and semi-solid pharmaceutical preparations. According to USP <429> "Particle Size Distribution Estimation by Laser Diffraction," this method is appropriate for polydisperse systems and is especially useful in the analysis of pharmaceutical and biological products where accurate and rapid characterization of particle size is required.

[0134] The use of the SALD-2300 is justified not only by its compliance with pharmacopeial specifications but also due to its ability to deliver reproducible, high- resolution results without the need for destructive techniques, thereby preserving the integrity of the sample throughout the analysis.

[0135] The SALD-2300 employs laser diffraction technology to determine particle size. This method is based on the principle that particles scatter laser light at angles inversely proportional to their size: larger particles scatter light at smaller angles, while smaller particles scatter at wider angles.

[0136] The instrument detects the scattering pattern and, using mathematical models (Mie or Fraunhofer theory), calculates the particle size distribution, typicallyreported as an equivalent spherical diameter.

[0137] This is a rapid, non-destructive, and precise technique, well-suited for polydisperse systems. It is recognized by major pharmacopeias, including the USP and Ph. Eur., for use in the analysis of pharmaceutical and biological products.

[0138] The medicinal product was prepared for this test in two different ways for each sample of Trabumag and Tramadol HCI. For the Trabumag sample, a single tablet (958 mg per tablet) was used per technique, with three repetitions per method, totaling six tablets. Three of these were crushed using a manual kitchen mortar (identified in the graphic as Trabumag kitchen mortar), and the other three were pulverized using an electric coffee grinder (identified in the table as Trabumag coffee grinder). To each sample, 10 mL of deionized water was added.

[0139] For the Tramadol HCI sample, three tablets were used per repetition (205 mg per tablet), with three repetitions per technique, totaling 18 tablets. Nine of these were crushed using a manual kitchen mortar (identified in the graphic as Tramadol HCI 3 tablets kitchen mortar), and the remaining nine were ground using an electric coffee grinder (identified in the table as Tramadol HCI 3 tablets coffee grinder). Again, 10 mL of deionized water was added to each sample.

[0140] Additionally, six samples of Tramadol HCI were prepared using only one tablet per sample, following the same crushing technique with both a manual kitchen mortar and an electric coffee grinder. These samples were identified in the same manner, with the only difference being the number of tablets used, one in this case. A total of 18 samples were analyzed. Results are shown in fig. 2 - 5.

[0141] Figures 2-3 show the particle size distribution for Trabumag samples after grinding with a mortar and a grinder. Both manual and mechanical grinding resulted in particle distributions in the medium to large size range, but the grinder produced a greater proportion of smaller particles, indicating more efficient fragmentation. Figures 4-5 show Tramadol HCI tablets ground using three or one tablet at a time. As with Trabumag, the grinder resulted in significantly smaller particles compared to the mortar. Additionally, grinding a larger number of tablets (three vs. one) led to more uniform and predictable particle distributions.

[0142] Trabumag generates larger particles after crushing, indicating greatermechanical resistance - beneficial from an ADF perspective. Tramadol HCI is more easily crushed into smaller particles, which may encourage abuse. A mechanical grinder produces more effective crushing, but Trabumag still demonstrates partial resistance to this processing method.

[0143] The measurement of the powder volume after grinding

[0144] The measurement of the powder volume obtained after tablet crushing is a critical parameter in the evaluation of Abuse-Deterrent Formulations (ADF). According to guidelines established by pharmacopoeias such as the United States Pharmacopeia (USP) and the European Pharmacopoeia, this test is part of the mechanical manipulation studies used to characterize the physical tamper-resistance of solid oral dosage forms.

[0145] The primary objective is to assess whether, after crushing using common household methods (e.g., manual mortars or electric grinders), the resulting powder volume facilitates or hinders potential non-medical routes of administration, such as intravenous injection or intranasal insufflation. ADFs are specifically designed to yield a large, cohesive, or clumping mass upon tampering, making it difficult to manipulate or dissolve the product for abuse purposes.

[0146] Therefore, evaluating the powder volume post-crushing is an essential tool for confirming a formulation's resistance to manipulation and potential misuse, in accordance with both regulatory requirements and patient safety standards.

[0147] The equipment used to crush the tablets included a manual stone kitchen mortar and an electric coffee grinder (brand: AmazonBasics, model: CG9402CE) and 5 mL graduated cylinder.

[0148] The medicinal product was prepared for this test in two different ways for each sample of Trabumag and Tramadol HCI. For the Trabumag sample, a single tablet was used per technique, with three repetitions per method, totaling six tablets. Three of these were crushed using a manual kitchen mortar (identified in the table as Trabumag after kitchen mortar), and the other three were pulverized using an electric coffee grinder during 30 seconds (identified in the table as Trabumag after coffee grinder).

[0149] For the Tramadol HCI sample, three tablets were used per repetition, with three repetitions per technique, totaling 18 tablets. Nine of these were crushed using a manual kitchen mortar (identified in the table as Tramadol HCI after kitchen mortar), andthe remaining nine were ground using an electric coffee grinder during 30 seconds (identified in the table as Tramadol HCI after coffee grinder).

[0150] Table 15. Trabumag and Tramadol HCI: Density of powder

[0151] Table 16. Trabumag and Tramadol HCI: Evaluation of loss

[0152] Trabumag tablets, when crushed, produce a powder with a larger volume and lower density, making it difficult to process further (e.g., for injection). Tramadol HCI tablets produce a more compact powder (powder density up to 698.63 mg / mL) and lower volume, which may facilitate handling.

[0153] Conclusion: The larger volume and lower density of the Trabumag powder provide value in preventing abuse, especially considering the difficulties in dissolving and filtering the large-volume powder.

[0154] Osmolarity

[0155] The analysis of osmolarity in medicinal products is a critical parameter in the quality control and safety assessment of pharmaceutical formulations, particularly those intended for parenteral, ophthalmic, or nasal administration. According to the standards established by major pharmacopoeias such as the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP), osmolarity must be carefully evaluated to ensure that the formulation is physiologically compatible and does not cause cellular damage, irritation, or adverse systemic effects upon administration.

[0156] An inappropriate osmolarity can lead to hemolysis, tissue irritation, or compromised therapeutic efficacy, especially in intravenous or subcutaneous products. For this reason, regulatory authorities require that the osmolarity of solutions be within acceptable physiological ranges (typically 270-330 mOsm / L for injectable products), unless specifically justified.

[0157] Monitoring osmolarity also plays an important role in the design of abusedeterrent formulations (ADFs), where altered osmotic profiles may discourage inappropriate routes of administration. Overall, osmolarity testing ensures the safety, tolerability, and therapeutic integrity of medicinal products, supporting both patientcompliance and regulatory compliance.

[0158] Osmolarity was measured using a freezing point depression osmometer (Model 3250 Osmometer, Advanced Instruments). This instrument determines osmolarity by measuring the freezing point of the sample solution, which decreases proportionally with the concentration of osmotically active particles. During the analysis, a small aliquot of the sample is supercooled, and then crystallization is induced. The device precisely records the temperature at which the solution freezes, and this value is used to calculate the osmolarity in milliosmoles per liter (mOsm / L). This method is in accordance with pharmacopoeial guidelines for osmolarity testing of pharmaceutical solutions.

[0159] The medicinal product was prepared for this test in two different ways for each sample of Trabumag and Tramadol HCI. For the Trabumag sample, a single tablet was used per technique, with three repetitions per method, totaling six tablets. Three of these were crushed using a manual kitchen mortar (identified in the table as Trabumag after kitchen mortar), and the other three were pulverized using an electric coffee grinder during 30 seconds (identified in the table as Trabumag after coffee grinder).

[0160] For the Tramadol HCI sample, three tablets were used per repetition, with three repetitions per technique, totaling 18 tablets. Nine of these were crushed using a manual kitchen mortar (identified in the table as Tramadol HCI after kitchen mortar), and the remaining nine were ground using an electric coffee grinder during 30 seconds (identified in the table as Tramadol HCI after coffee grinder).

[0161] Additionally, a Tramadol HCI sample was prepared using a single tablet to verify the accuracy of the ratio. The preparation followed the same procedure described for the kitchen mortar method, with the only modification being the use of one tablet instead of three. Results are shown in tables 17-19 below.

[0162] Table 17. Osmolarity in Trabumag

[0163] Table 18. Osmolarity in Tramadol HCI 3 tablets

[0164] Table 19. Osmolarity in Tramadol HCI 1 tablet

[0165] The Trabumag formulation demonstrated osmolarity values ranging from 544 to 606 mOsm / L. According to abuse-deterrent formulation (ADF) principles, such osmolarity levels are considered acceptable, particularly given that the product is intended for oral administration, where elevated osmolarity does not pose a safety concern under normal use.

[0166] However, it is important to acknowledge the potential risks associated with parenteral abuse. While osmolarity values in this range may contribute to deterrence effects, such as pain and irritation upon injection, they may also carry a risk of vascular damage if misuse occurs. Therefore, further evaluation of potential local tissue effectsand intravenous tolerability would be warranted to fully assess the safety profile in the context of ADF design.

[0167] In contrast, the Tramadol HCI formulation, in both the three-tablet and one- tablet samples, showed osmolarity values below the physiological range (approximately 280-310 mOsm / L), indicating that these solutions are hypotonic. While this may not present an immediate risk under therapeutic conditions, it suggests low deterrent potential via osmolarity and highlights the need for additional abuse-deterrent mechanisms if tamper resistance is desired.

[0168] Checking whether the suspension passes through a syringe equipped with a 0.8mm, 0.9mm and 1 .2mm diameter needle.

[0169] The assessment of aspiration and ejection performance using standardized needles, such as 0.9 mm diameter needles (20G), is a critical quality control procedure for pharmaceutical solutions intended for parenteral use. This test ensures that the formulation can be safely and effectively drawn up and administered without clogging, which is particularly important for products intended to be handled with manual syringes by healthcare professionals.

[0170] According to the requirements set forth by major international pharmacopoeias, including the European Pharmacopoeia and the United States Pharmacopeia (USP), this test verifies that the product does not contain precipitates, excessive viscosity, or particulate matter that could hinder its passage through commonly used clinical needles. Additionally, it helps ensure dose uniformity, device compatibility, and ultimately patient safety.

[0171] Needles of 1.2 mm, 0.9 mm, and 0.8 mm of diameter were used, along with a 5 mL syringe.

[0172] Two solutions of Trabumag were prepared (one using a manual kitchen mortar and the other using an electric coffee grinder during 30 seconds, each with a single tablet), and two solutions of Tramadol HCI were prepared in the same manner (one using a manual kitchen mortar and the other using an electric coffee grinder during 30 seconds, each with a single tablet). All samples were dissolved in 10 mL of deionized water.

[0173] The results demonstrated that, across all three needle gauges tested, both types of solutions in their respective forms (prepared using a kitchen mortar or an electriccoffee grinder) did not impede the aspiration or injection of the tested pharmaceutical products. The only observed adverse effect during the test was a slight resistance during aspiration and ejection when using the 0.8 mm diameter needle; however, this did not prevent successful aspiration or administration of the solution at any point.

[0174] As a positive aspect, this solution exhibits low solubility, as it precipitates rapidly and produces visible sediment, which may result in reduced tissue diffusion upon attempted parenteral administration.

[0175] Viscosity

[0176] The viscosity measurement requirements outlined in the European Pharmacopoeia (Ph. Eur.), the United States Pharmacopoeia (USP), and the Polish Pharmacopoeia focus on ensuring the accuracy and repeatability of results, particularly for liquid pharmaceutical products. These pharmacopoeias specify that viscosity measurements must be conducted under defined conditions using appropriate instruments, such as rotational, capillary, or falling-ball viscometers, suited to the type of liquid being tested. A rotational viscometer measures viscosity based on the resistance a liquid offers to a rotating spindle; the force required to overcome this resistance is proportional to the viscosity of the liquid, enabling precise measurement.

[0177] The viscosity testing was performed using the IKA ROTAVISC lo-vi Complete rotational viscometer, which is especially recommended by the Pharmacopoeia for measuring the viscosity of non-Newtonian fluids, whose viscosity changes with shear rate (such as pharmaceutical suspensions and emulsions). The European Pharmacopoeia specifies that these instruments must provide precise control over parameters such as rotational speed and temperature, and ensure an accuracy of ±1 %, which is consistent with the ROTAVISC specifications.

[0178] Viscosity was measured using the ROTAVISC lo-vi (IKA) rotational viscometer equipped with the VOL-SP-6.7 spindle, which allows for viscosity measurements in the range of 1.5-29,994 mPas (200 rpm-0.1 rpm). Measurements were conducted at 20°C.

[0179] Test Sample: The medicinal product was prepared for this test in two different ways for each sample of Trabumag and Tramadol HCI. For the Trabumag sample, a single tablet was used per technique, with three repetitions per method, totalingsix tablets. Three of these were crushed using a manual kitchen mortar (identified in the table as Trabumag kitchen mortar), and the other three were pulverized using an electric coffee grinder during 30 seconds (identified in the table as Trabumag coffee grinder). To each sample, 10 mL of deionized water was added.

[0180] For the Tramadol HCI sample, three tablets were used per repetition, with three repetitions per technique, totaling 18 tablets. Nine of these were crushed using a manual kitchen mortar (identified in the table as Tramadol HCI kitchen mortar), and the remaining nine were ground using an electric coffee grinder during 30 seconds (identified in the table as Tramadol HCI coffee grinder). Again, 10 mL of deionized water was added to each sample.

[0181] Table 20. Viscosity Results for the Tested Samples

[0182] The viscosity values obtained for both TrabumagTrabumag and Tramadol HCI solutions were similar to each other and close to the viscosity of water, which is approximately 1 mPa s at room temperature. This indicates that both formulations behave essentially as aqueous solutions of Tramadol, without significant thickening or increase in viscosity. Consequently, TrabumagTrabumag does not exhibit any notable abusedeterrent properties related to viscosity, and it would not pose additional resistance or difficulty in administration via injection compared to the standard Tramadol HCI solution.

[0183] Measurement of the solution's pH (10 ml water suspension)

[0184] The determination of pH in pharmaceutical formulations is a critical quality attribute mandated by major pharmacopoeias, including the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP). Accurate pH measurement of a tablet dispersed or dissolved in a defined volume (such as 10 mL of deionized water) is essential for ensuring stability, solubility, and bioavailability, as well as for predicting local tolerability at the site of administration.

[0185] In the context of abuse-deterrent formulations (ADFs), pH analysis also plays a strategic role. Formulations designed to deter non-oral routes of administration (e.g., intravenous or intranasal abuse) may employ extreme or non-physiological pH levels to induce irritation, precipitation, or injection difficulty when manipulated improperly. Evaluating the pH after dissolving a single tablet in a small volume of water (e.g. , 10 mL) simulates potential misuse scenarios and helps assess the deterrent effectiveness of the formulation.

[0186] Furthermore, pharmacopoeial guidelines require that pH remain within an acceptable and safe physiological range when intended for oral use, while still allowing for ADF-specific pH adjustments that discourage tampering or alternative administration routes. Thus, pH analysis serves both as a regulatory requirement and as a key tool in ADF development and risk assessment.

[0187] The pH of the samples (TrabumagTrabumag, Tramadol HCI 3 tablets, and Tramadol HCI 1 tablet) was analyzed using a Mettler Toledo pH meter. This instrument determines pH through the use of a combined glass electrode, which measures thehydrogen ion activity in the solution. The device operates by detecting the voltage difference generated between a reference electrode and a pH-sensitive measuring electrode immersed in the sample. The resulting potential is converted into a pH value, providing accurate and reliable results in accordance with pharmacopoeial standards.

[0188] The use of varying the number of control tablets (1 vs. 3) in the pH section was used to analyze the effect of the concentration of the active ingredient and excipients on the solution's pH.• 1 tablet: simulates a therapeutic situation or potential sample dilution (lower concentration).• 3 tablets: simulates a tampering attempt (higher concentration of active ingredients and excipients), which may alter the solution's pH and affect its compliance with pharmacopoeial requirements or its irritating properties.

[0189] Conclusion: Varying the number of tablets was used to assess the effect of concentration on the pH value, which is important for assessing the risk of abuse.

[0190] The medicinal product was prepared for this test in two different ways for each sample of TrabumagTrabumag and Tramadol HCI. For the TrabumagTrabumag sample, a single tablet was used per technique, with three repetitions per method, totaling six tablets. Three of these were crushed using a manual kitchen mortar (identified as TrabumagTrabumag after kitchen mortar), and the other three were pulverized using an electric coffee grinder (identified in the table as TrabumagTrabumag after coffee grinder). To each sample, 10 mL of deionized water was added.

[0191] For the Tramadol HCI sample, three tablets were used per repetition, with three repetitions per technique, totaling 18 tablets. Nine of these were crushed using a manual kitchen mortar (identified in the graphic as Tramadol HCI 3 tablets after kitchen mortar), and the remaining nine were ground using an electric coffee grinder (identified in the table as Tramadol HCI 3 tablets after coffee grinder). Again, 10 mL of deionized water was added to each sample.

[0192] Additionally, six samples of Tramadol HCI were prepared using only one tablet per sample, following the same crushing technique with both a manual kitchen mortar and an electric coffee grinder. These samples were identified in the same manner,with the only difference being the number of tablets used — one in this case. A total of 18 samples were analyzed. Results are shown in table 20.

[0193] Table 20. Evaluation of pH in Trabumag and Tramadol

[0194] The pH values obtained for the tested formulations, ranging from 4.98 to 6.64, are considered acceptable for oral administration, as they fall within the physiologically tolerated range and comply with pharmacopoeial guidelines. While these values are not extreme enough to independently serve as a strong abuse-deterrent mechanism (e.g., through injection site irritation or tissue damage), they are compatible with the development of an ADF (Abuse-Deterrent Formulation) when integrated into a multifactorial strategy. This may include additional deterrent features such as high osmolarity, increased viscosity, gelling upon tampering, or reduced solubility, all aimed at discouraging non-oral routes of misuse.

[0195] Determination of Tramadol Content Using High-Performance Liquid Chromatography (HPLC) with UV-VIS Detection

[0196] Reagents:• Acetonitrile, Sigma, Cat. No.: 1.00029.25, Batch: 11185829 150• Formic acid, Sigma

[0197] Test solution: The samples were prepared following the manual triturating method using a kitchen mortar for both types of tablets, Trabumag and Tramadol HCI, with one tablet of each type per solvent. Once triturated, the powder was transferred to a 10 mL volumetric flask, where the corresponding solvent (as specified in the table) wasadded up to the 10 mL mark. The solution was then mixed thoroughly and filtered through 150 mm coffee filters. Subsequently, 30 pL of the prepared sample was taken and diluted with water to a final volume of 1500 pL. The mixture was vortexed, filtered through a 0.45 pm PTFE syringe filter, and analyzed.

[0198] Table 20. Solvents used for extraction

[0199] Calibration Curve: Weigh 10 mg of the reference standard into a 10 mL volumetric flask, fill to the mark with water, and mix thoroughly. Then prepare dilutions according to the table below.

[0200] Table 21. Calibration curve dilutions

[0219] Chromatographic SystemMobile Phase A: 0.1 % formic acid in waterMobile Phase B: 0.1 % formic acid in acetonitrileColumn: Luna C18 (5 pm), 250 x 4.6 mmColumn oven temperature: 30°CFlow rate: 1.5 mL / minInjection volume: 20 pLUV detection: 270 nmElution mode: Gradient

[0220] Table 22. Chromatographic System

[0201] The tramadol content in mg per tablet was calculated based on reference solution C using the following formula:Pp - Peak area of tramadol in the test sample mw - Weight of the reference standard of aripiprazole, mgP - Potency of the reference standard, % m - Average tablet weight, mgPw - Peak area of tramadol in the reference solution n - Sample weight, mg

[0209] Results are presented in table 23 and calibration curve is presented on fig.

[0202] Table 23. Summary of tramadol concentration

[0203] The extraction process using different solvents and paper coffee filters demonstrated that the extraction of tramadol from both tablet types (the standard Tramadol HCI tablet and the ADF formulation Trabumag) is nearly complete. It is important to consider potential losses during the extraction process, which are estimated at approximately 4.89 % in Trabumag and 3.01 % in Tramadol HCI when employing the manual triturating technique with a kitchen mortar.

[0204] During extraction, it was observed that the volume obtained after filtration was reduced and the filtration time was somewhat longer for the Trabumag formulation, especially with solvents containing alcohol groups in their structure (see photos 1 and 2). This suggests that interaction with magnesium lactate may retain part of the tramadol, thereby limiting its extraction. Nonetheless, analytical results indicate that tramadol extraction is practically complete in both formulations. Therefore, the ADF formulation Trabumag does not exhibit properties that protect tramadol from extraction by solvent.

[0205] Properties of ADF in a formulation containing piperineThe piperine-containing formulation was developed according to the same technological assumptions as the Trabumag product presented in the report, meaning it retains all the abuse-deterrent properties (ADF) described in this document. The vehicle components and manufacturing process remain identical, and the addition of piperine does not negatively impact parameters such as tablet hardness, powder volume and density after grinding, osmolarity, pH, or syringeability - as confirmed by parallel physicochemical studies. Importantly, piperine is insoluble in water, further complicating the handling of the product for parenteral administration (e.g., intravenous or intranasal injection). Its presence causes significant turbidity of the solution, particle sedimentation, and rapid destabilization of the suspension. Piperine particle size is in the 50-80 pm range, which is a significant safety factor - particles of this size can clog capillaries, leading to embolism and potential complications during intravenous administration. Additionally, piperine has an irritating and stinging effect on mucous membranes, significantly limiting the possibilityof using the preparation intranasally (e.g., by snorting the powdered product). Manipulations related to suspension injection are also difficult, both due to its low solubility and negative local effects (burning, inflammation). Therefore, the presence of piperine in the formulation not only does not impair the properties of ADF but actually enhances its anti-abuse effect through mechanical (particle size), physicochemical (poor solubility), and sensory (irritation) effects.

[0206] Extractability studies for a formulation containing piperineExtractability studies were conducted for the formulation containing piperine under conditions analogous to those for formulations containing only tramadol. The results clearly indicate that the presence of piperine does not significantly affect the amount of extracted opioid, regardless of the solvent used. However, significant differences are observed in the physicochemical properties of the extracts obtained, in particular:• In water and aqueous solutions (e.g., buffers, soft drinks), the extracts obtained are noticeably turbid, which results from the fact that piperine is insoluble in aqueous media. Suspension of piperine creates a persistent turbidity and significantly reduces the clarity of the solution, which can act as a deterrent to manipulation.• When ethanol and ethanol solutions with concentrations of 96-40% are used, clear solutions are produced, but with a very intense, stinging, burning taste. This strong sensory effect constitutes a significant barrier to non-medical routes of administration (e.g., intranasal or oral administration in excessive amounts). In solutions with ethanol concentrations below 40%, turbidity of the extracts and a persistent, irritating taste are observed again. During filtration, the filtrate remains opalescent. Piperine does not limit the extraction of tramadol; however, it significantly alters the organoleptic and physicochemical properties of the extracts, which can be considered a factor supporting the abuse-deterrent effect (ADF).

[0207] Syrinqeabi litv for a formulation containing piperineFor formulations containing piperine, syringeability tests were performed using needles with a diameter of 0.8-0.9 mm. The resulting suspensions, prepared by crushing the tablet and suspending it in 10 mL of water, did indeed pass through the needles. However,:• Piperine forms a stable suspension system in an aqueous environment with particles measuring 50-80 pm, which poses a significant clinical risk. Such large particles can clog capillaries and lead to local thrombotic or embolic complications if administered parenterally.• Additionally, suspensions containing piperine (even after filtration) cause a very strong stinging / burning sensation at the injection site, which was confirmed under model conditions. This effect may be related to the direct irritating effect of piperine on soft tissues. Although piperine suspensions are technically injectable, they generate significant health risks and discomfort, which effectively discourages their non-medical use.

[0208] ADF-Supportinq Properties for a formulation containq piperineIn addition to the above-mentioned aspects, it was also confirmed that the addition of piperine does not negatively affect the key physicochemical parameters of the formulation:• Tablet hardness remains above 200 N, meeting pharmacopoeial requirements for formulations with increased mechanical resistance (ADF).• The pH and osmolarity of the solutions are within the safe range for oral administration, but do not meet the requirements for parenteral administration - further supporting the abuse prevention profile.

[0209] ConclusionsThe presence of piperine significantly improves the safety profile in the context of potential abuse:• by reducing the attractiveness of the extracts (turbidity, burning sensation),• by increasing the risk of intravenous administration (suspension with 50-80 pm particles),• and by unpleasant sensory effects (severe burning sensation, irritation). Thus, piperine acts as a functional component supporting ADF, especially with regard to sensory, mechanical and physicochemical barriers.

[0210] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and the scope of theappended claims.

[0211] A solid, analgesic dosage form for oral administration with abuse-deterrent properties, said dosage form comprises: one or more active ingredients having potential for abuse selected from the group consisting of Alfentanil, Benzhydrocodone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Fentanyl, Hydrocodone, hydrocodone bitartrate, Hydromorphone, Levorphanol tartrate, Meperidine hydrochloride, Methadone, Morphine, Normethadone, Opium, Oxycodone, Oxymorphone, Pentazocine, Tapentadol, Tramadol, TEV-90105, ELI-202, or pharmaceutically acceptable salts and solvates thereof; and magnesium salt selected from the group consisting of consisting of Magnesium acetate, Magnesium benzoate, Magnesium bromate, Magnesium bromide, Magnesium carbonate, Magnesium chlorate, Magnesium chloride, Magnesium chromate, Magnesium citrate, Magnesium fluoride, Magnesium fluorosilicate, Magnesium formate, Magnesium glycinate, magnesium hydroaspartate, Magnesium hydroxide, Magnesium iodate, Magnesium iodide, Magnesium lactate, Magnesium L-threonate, Magnesium Malate, Magnesium molybdate, Magnesium nitrate, Magnesium oxalate, Magnesium oxide, Magnesium perchlorate, Magnesium phosphate, Magnesium selenite, Magnesium sulfate, Magnesium sulfate heptahydrate, Magnesium sulfite, Magnesium thiosulfate or a combination thereof.

[0212] The dosage administered through intravenous injection increases osmolarity and alters pH of the extract, therefore producing pain and irritation at the injection site and discouraging abuse.

[0213] The dosage administered through nasal mucosa produces an unpleasant local sensation and discourage abuse.

[0214] The dosage comprises a mass ratio of active ingredient to magnesium salt of ranging from 0.15 :1 to 4: 1 .

[0215] The dosage comprises a mass ratio of active ingredient to magnesium salt to piperine of ranging from 0.15 :1 to 4:1 to 0.01 :1.

[0216] The dosage has one or more active ingredients that have potential for abuse, comprise less than 20%, and preferably less than 10% of the composition by mass.

[0217] The dosage has magnesium salt comprising 50-80% of the composition by mass.

[0218] The dosage is compressed in a tablet.

[0219] The foregoing disclosure and description of the invention is illustrative and explanatory thereof. Various changes in the details of the illustrated structures, construction and method can be made without departing from the true spirit of the invention.

Claims

Claims1. A solid, analgesic dosage form for oral administration with abuse deterrent properties, said dosage form comprising:(a) one or more active ingredients having potential for abuse selected from the group consisting of Alfentanil, Benzhydrocodone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Fentanyl, Hydrocodone, hydrocodone bitartrate, Hydromorphone, Levorphanol tartrate, Meperidine hydrochloride, Methadone, Morphine, Normethadone, Opium, Oxycodone, Oxymorphone, Pentazocine, Tapentadol, Tramadol, TEV-90105, ELI-202, or pharmaceutically acceptable salts and solvates thereof;(b) magnesium salt selected from the group consisting of consisting of Magnesium acetate, Magnesium benzoate, Magnesium bromate, Magnesium bromide, Magnesium carbonate, Magnesium chlorate, Magnesium chloride, Magnesium chromate, Magnesium citrate, Magnesium fluoride, Magnesium fluorosilicate, Magnesium formate, Magnesium glycinate, magnesium hydroaspartate, Magnesium hydroxide, Magnesium iodate, Magnesium iodide, Magnesium lactate, Magnesium L-threonate, Magnesium Malate, Magnesium molybdate, Magnesium nitrate, Magnesium oxalate, Magnesium oxide, Magnesium perchlorate, Magnesium phosphate, Magnesium selenite, Magnesium sulfate, Magnesium sulfate heptahydrate, Magnesium sulfite, Magnesium thiosulfate or a combination thereof.

2. The dosage of claim 1 , wherein said dosage comprises piperine, in a form of extract from piper nigrum or piper longum or synthetically produced substance.

3. The dosage of claim 1 or 2, wherein said dosage administered through intravenous injection increases osmolarity and alter pH of the extract therefore producing pain and irritation at the injection site and discourage abuse.

4. The dosage of claim 1 or 2, wherein said dosage administered through nasal mucosa produces an unpleasant local sensation and discourage abuse.

5. The dosage of claim 1 or 2 or 3 or 4, wherein comprises a mass ratio of active ingredient to magnesium salt of ranging from 0.15 :1 to 4: 1 .

6. The dosage of claim 1 or 2 or 3 or 4, wherein comprises a mass ratio of active ingredient to magnesium salt to piperine of ranging from 0.15 :1 to 4:1 to 0.01 :1.

7. The dosage according to any of previous claims 1 -4, wherein the one or more active ingredients having potential for abuse comprises less than 20%, and preferably less than 10% of the composition by mass.

8. The dosage according to any of previous claims 1 -5, wherein magnesium salt comprises 50-80% of the composition by mass.

9. The dosage according to any of previous clams 1 -6, wherein the dosage is compressed in a tablet.

10. The dosage according to claim 9, wherein it has an osmolarity 544 to 606 mOsm / L.11 . The dosage according to claim 9 or 10, wherein it has a pH ranging from 6.3 to 6.64.

12. The dosage according to any of previous claims 9-11 , wherein it exceeded the hardness threshold of 150 N.

13. The dosage according to claim 12, wherein it has hardness ranging from 192 to 279 N.48

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