WO2022250523A1 - Pharmaceutical kits and products comprising a direct precursor in the formation of glycosaminoglycans and a non-steroidal anti-inflamatory drug as independent compositions, and uses of same - Google Patents

Abstract

The present invention relates to the development of independent compositions of active pharmaceutical ingredients that are usually combined into a single pharmaceutical form. In particular, the present invention relates to a kit comprising independent pharmaceutical compositions that have a disproportionate ratio in terms of quantity of active ingredients, which implies a potential risk for the health of patients due to the intrinsic actions of each active ingredient. The independent compositions enable patients in need to be dosed in an effective, uniform, safe and protected manner without the possibility of producing degradation substances, in addition to favouring the adaptability and performance of the pharmaceutical product given the possibility of being administered in scheduled dosing periods.

Description

PRODUCTS, PHARMACEUTICAL KITS AND THEIR USES INCLUDING A DIRECT PRECURSOR IN THE FORMATION OF GLYCOSAMINOGLYCANS AND A NON-STEROID ANTI-INFLAMMATORY DRUG AS COMPOSITIONS

INDEPENDENT

Field of Invention

The present invention relates to kits and pharmaceutical products that are packaged with independent compositions of active pharmaceutical ingredients. In particular, the present invention relates to a kit comprising independent pharmaceutical compositions that preferably have a relevant disproportionate ratio between the amount of doses of their active ingredients, which typically have associated problems when formulated together in a single dosage form. In addition, the kit of the present invention provides efficient, uniform and safe doses without the possibility of developing degradation substances, in addition to promoting the adaptability and performance of the pharmaceutical product due to the possibility of being delivered during the planned dosing periods.

The present invention also provides a method of using the kit, eg, the compositions.

Background of the Invention

There are currently different pharmaceutical compositions that contain the combination, in a single dosage form, of two or more related active ingredients. For example, patent MX326860 reveals a pharmaceutical composition, characterized in that it comprises the synergistic combination of active ingredients: Glucosamine and Meloxicam, where Glucosamine is in quantities of 100 mg to 3,000 mg or 750 mg and 1,500 mg of Sulfate. of Glucosamine and Meloxicam is in amounts of 0.1 mg to 15 mg, as well as pharmaceutically acceptable excipients. In addition, there is patent MX 268712 that describes a pharmaceutical composition in the form of coated microspheres characterized in that the coated microspheres comprise: a) inert nuclei covered with a first film made up of a muscle-relaxing drug, at least one adhesive polymer and at least one agent plasticizer; b) a second retarding polymeric film and at least one plasticizing agent; and c) a third film made up of an NSAID drug, the muscle relaxant drug of the first film, at least one adhesive polymer, at least one plasticizing agent and at least one surfactant; wherein the muscle relaxant drug has modified release and the NSAID drug has immediate release. The pharmaceutical composition of claim 1, wherein the muscle relaxant drug is tizanidine and the NSAID drug is meloxicam, or pharmaceutically acceptable salts thereof.

As can be seen, the compositions that try to solve the same technical problem are in unitary dosage forms, which causes that during the stay On the product shelf there may be degradation products or, worse still, adverse reactions due to the disparity in the number of administered doses of the two or more active ingredients.

Summary of the Invention

The following description details the best modes contemplated for carrying out the invention thus far. Therefore, this description should not be taken in a limiting sense but is made simply for the purpose of illustrating the general principles of the invention. The scope of the invention is better defined by the appended claims.

The development of any pharmaceutical composition is subject to the quality, safety, and efficacy of the formulation when used or administered to a patient for the treatment of any medical condition. In this sense, the development of pharmaceutical products or compositions must be aimed at ensuring stability and uniformity, particularly in products that comprise a combination of disproportionate doses of active pharmaceutical ingredients.

In one aspect, the present invention provides stand-alone pharmaceutical compositions to address the lack of safety, quality, efficacy, and uniformity of medications that comprise a combination of at least two pharmaceutical ingredients (known in the art to be dosed in combination in a single dosage form). , as well as improve the bioavailability, adaptation and performance of the active principles when they are consumed by a patient.

In another aspect, the present invention aims to reduce or simplify the manufacturing process of pharmaceutical compositions with a disproportionate presence or combination of at least two active pharmaceutical ingredients in order to improve a more homogeneous distribution, avoiding problems related to separation, reducing considerably the possibility of variation in the proportion and, consequently, simplify the process of packaging the product.

A further technical problem solved by the present invention is to avoid possible risks in the stability of the pharmaceutical compositions, in particular during the shelf life. The physical separation of active ingredients and/or pharmaceutical active ingredients considerably reduces the risk of product degradation because said formulations do not come into contact or interact with each other until they are used.

Another aspect of the present invention is to promote the bioavailability, the therapeutic adherence of the patient and the performance of the pharmaceutical compositions, since the development and administration of independent compositions will help the patient to consume the required dose, seeking the benefit and, consequently, , reducing the side effects of the pharmaceutical compositions based on a planned dosage. Brief description of the Figures of the Invention Figure 1 is a schematic of the administration of Glucosamine according to the exemplary protocol in the present invention.

Figures 2A and 2B show the thermograms (DSC) of the evaluation of Glucosamine (A) and Meloxicam (B) as raw material.

Figure 3 shows the thermogram (DSC) of the evaluation of the Glucosamine-Meloxicam mixture.

Detailed description of the representative modalities of the invention

An exemplary non-limiting embodiment of the present invention is a kit of independent compositions comprising a Glucosamine independent composition and a Meloxicam independent composition for the treatment of osteoarthritis. Consequently, said combination has been selected as a preferred embodiment of the present invention since the amount of both assets is 100:1, that is, 1500 mg of Glucosamine per 15 mg of Meloxicam. In addition, as described below, the separation of both active ingredients and their subsequent administration to a patient to treat osteoarthritis at specific and/or planned times contributes to considerably reducing the side effects caused to the patient. It should be noted that this exemplary modality should not be construed as limiting the invention, on the contrary, the exemplary modality of Glucosamine and Meloxicam comprises a deep understanding of the type of combinations with susceptibility to the application of the present invention; therefore, any current pharmaceutical composition in combination with at least two active pharmaceutical ingredients can be used and considered within the scope and spirit of the present invention.

Typical embodiments of exemplary compositions include one or more pharmaceutically acceptable excipients comprising, among others, diluents, disintegrants, binders, and lubricants. Preferably, the excipients comply with National Formulary ("NF") or United States Pharmacopeia ("USP") standards. In a particular embodiment, the compositions include one or more diluents, disintegrants, binders, and lubricants.

The person skilled in the art will now understand that when the pharmaceutical compositions include combinations with a disproportionate ratio in the amount of active principles, the risk of possible unwanted side effects or adverse interactions increases, as well as a potential generation of degradation substances that imply a potential risk to the health of the patient.

The Glucosamine-Meloxicam association is focused on treating and stopping the progression of osteoarthritis (DMOAD/SYSADOA); The chondroprotective and restorative effect of Glucosamine, together with the anti-inflammatory and analgesic action of Meloxicam, significantly relieve pain, both at rest and in movement, improving mobility in the short and medium term. In general terms, the combination of said compositions offers a fast action symptomatic that leads to the process of stopping the progression of osteoarthritis. However, glucosamine intake is known to affect glucose metabolism, thus tending to increase glucose levels and causing insulin resistance through activation of the hexosamine biosynthetic pathway. Glucosamine does not adversely affect glycemic control in the short term in patients with controlled diabetes or without diabetes or glucose intolerance; however, Glucosamine may worsen glucose intolerance in patients who are not on regular treatment or who have not yet been diagnosed.

With reference to Meloxicam, its administration can cause adverse effects, particularly gastrointestinal conditions such as peptic ulcers and bleeding. Meloxicam is an NSAID and therefore side effects may focus on the barrier properties of the stomach, since a luminal pH less than 2, like the stomach under fasting conditions, the mucosal gel layer breaks down and deteriorates. gastric conditions, leading to the development of erosions and increased permeability, ultimately leading to a total disruption of the extracellular lipid layers and membranes that protect the gastrointestinal tract from acid backdiffusion, and ultimately the development of a gastroduodenal ulcer with complications associated with bleeding and obstruction; So when this drug is prescribed, the doctor knows the importance of a uniform and stable dose within the permitted therapeutic scheme.

When Glucosamine is administered to a patient before food consumption, it prevents or avoids the increase in glucose levels related to the intrinsic action of this active ingredient; Likewise, it has been found that when Meloxicam is administered to a patient along with or after food intake, considering that the duodenal pH during meals ranges from 5.17 to 6.10 and the gastric pH rises to 5.5, rupture is avoided. of the mucous layer of the stomach, the development of erosions and gastroduodenal ulcers derived from the intrinsic action of Meloxicam.

To solve the above pharmacological problems, both glucosamine and meloxicam should be sold in a single pharmaceutical, but as separate compositions that are not in physical contact or mixed in any way with each other. This can be achieved by packaging Glucosamine and Meloxicam in any suitable container, such as sachets, plastic containers, bags, sachets, and/or sacks, etc.

Therefore, the present invention proposes to develop kits that comprise independent compositions for the combination of Glucosamine-Meloxicam and others in the same dose discrepancy to increase efficacy and reduce or circumvent the aforementioned associated complications.

Administration in stand-alone dosage form can provide a simple, safe and efficient solution to administer a pharmaceutical active to a patient based on, for example, the time of day, the period of food intake, the type of physical activity performed by the patient, among others, taking into account the pharmacodynamics of the compositions, it is that is, to administer the drug when it is suitable for the organism of the patient.

In the exemplary embodiment, when glucosamine is administered to a patient prior to food intake, there is little or no action on glucose metabolism other than that inherent in the food consumed and, in the case of Meloxicam, the Administration can be at any time, since the bioavailability of this formulation is not influenced by the concomitant intake of foods, even with high fat content, on the contrary, the benefit of consuming Meloxicam after intake is directed entirely to protection. of the gastric mucosa as a consequence of the increase in pH after the consumption of food.

On the other hand, the present invention also reduces the potential for incompatibility derived from the combination of at least two active pharmaceutical ingredients, where said at least two compositions present a disproportionate combination with each other; in this sense, when developing independent compositions within a kit according to the present invention, the at least two active principles must not come into contact with each other, reducing or even eliminating the possibility of generating any degradation substance during the useful life and / or or administration, thus favoring the stability of the formulation and increasing patient safety.

In addition, the present invention simplifies the manufacturing and packaging process, so no process is necessary that involves the combination of the aforementioned compositions, a precision control process being necessary to guarantee the weight, quantities and percentages required of the compositions In this regard, by developing independent compositions in different containers, for example, and without being limited to sachets, containers, among other containers or suitable containers, regardless of their pharmaceutical form, the manufacture and dosage is facilitated and, consequently, it is ensured the correct administration to the patient. EXAMPLES

EXAMPLE 1 . Clinical protocol Therapeutic indication

Glucosamine combined with Meloxicam is indicated for the effective treatment of osteoarthritis, with an important effect on the repair and improvement of degenerated cartilage. Description of active ingredients and medicines

The pharmaceutical form of the drug is powder contained in two sachets:

1 sachet of Glucosamine contains: 1500 mg of powdered Glucosamine 1 sachet of Meloxicam contains: 15 mg of powdered Meloxicam

Glucosamine pharmacotherapeutic group: nonsteroidal anti-inflammatory and antirheumatic compounds.

Pharmacotherapeutic group of meloxicam: non-steroidal anti-inflammatory drugs. pharmacokinetics The pharmacokinetic properties of glucosamine are described below:

Absorption·.

After oral administration of ¹⁴ C-labeled glucosamine, systemic absorption in healthy volunteers was determined to be rapid and almost complete, 90%. Its absolute bioavailability is 44%, due to the hepatic effect that occurs as the first step.

In plasma, the pharmacokinetics of glucosamine was linear, indicating that absorption is not saturated at high doses.

Clinical trials were conducted in 12 healthy volunteers, maximum steady-state plasma concentrations (Cmax, ss) of 1602 ± 426 ng/mL were observed after repeated administrations of glucosamine sulfate (1500 mg once daily). The tmax ranged from 1.5 to 4 hours (mean 3 h). At steady state, the area under the plasma concentration versus time curve is about 14564 ± 4138 ngh/mL. These parameters have been obtained by fasting administration of glucosamine sulfate. No gender differences were found in humans with respect to the absorption and bioavailability of glucosamine.

Distribution

After oral absorption, glucosamine is widely distributed into extravascular compartments, including synovial fluid, with an apparent volume of distribution 37 times that of total body water in humans. Glucosamine has not been shown to bind to plasma proteins, therefore it is unlikely that glucosamine could cause drug displacement interactions when co-administered with drugs highly bound to plasma proteins.

Metabolism

Despite being an endogenous substance, the metabolic profile of glucosamine has not been studied; however, it is used as a basic element in the biosynthesis of the articular cartilage component, and it is mainly metabolized through the hexosamine pathway and is independent of the cytochrome enzyme system.

Crystalline glucosamine sulfate does not act as an inhibitor or inducer of human CYP450 (cytochrome P-50) isoenzymes including CYP3A4, CYP1A2, CYP2E1, CYP2C9, CYP2C19, and CYP2D6, even when glucosamine concentrations are 300-fold higher than normal concentrations. , are studied. Peak plasma levels observed in man after therapeutic doses of crystalline glucosamine sulfate. No clinically relevant metabolic inhibition and/or induction interactions are expected between crystalline glucosamine sulfate and other co-administered drugs that are substrates of human CYP450 isoforms.

Excretion

The elimination half-life (ti _/³ ) of glucosamine is estimated to be 15 hours. Behind the Oral administration of ^14C- labelled glucosamine, urinary excretion is of the order of 10 ± 9% of the administered dose while fecal excretion is 11.3 ± 0.1%. The mean urinary excretion of unchanged glucosamine after oral administration in humans was approximately 1% of the administered dose, suggesting that the kidneys and liver do not contribute significantly to the elimination of glucosamine and/or its metabolites.

The pharmacokinetic properties of Meloxicam are described below Absorption

After oral administration, Meloxicam is absorbed from the gastrointestinal tract, obtaining a bioavailability of approximately 89%. After ingesting a single 15 mg dose of meloxicam, peak plasma concentrations are generally obtained at 5:00 ± 3:00 hours and are 1064.8 ± 180.7 ng/mL.

Distribution :

Meloxicam is distributed in all organs and tissues, including liver, kidney, and synovial fluid (where it reaches concentrations of 40% to 50% of those obtained in plasma, crosses the blood-brain and placental barriers, and is even detectable in breast milk). It has a high protein binding, 99.40%, its apparent volume of distribution is 10 to 15 L. Metabolism:

Meloxicam undergoes extensive metabolism. CYP2C910 is the main enzyme responsible for biotransformation with minor contributions from CYP3A4. Meloxicam has 4 main metabolites, the main one being 5'-carboxymethylmeloxicam (60% of the dose is biotransformed into this metabolite). All the metabolites generated lack biological activity 5,6.

Excretion·.

Its excretion occurs via the kidneys (98.40%) where 0.25% is excreted as unchanged drug and the rest as metabolites. Urinary acidification does not modify drug reabsorption. The elimination half-life is 18.94 ± 4.99 hours.

pharmacodynamics

The chondroprotective action of glucosamine can be explained by a double mechanism:

The first is that the building blocks of cartilage and synovial fluid stimulate the anabolic process of cartilage metabolism. The second is due to the anti-inflammatory action that can delay many catabolic processes induced by inflammation in cartilage. Both mechanisms can regenerate the structure of the joint, reducing pain and increasing the mobility of the affected joint.

The effects of nonsteroidal anti-inflammatory drugs have been separated into three large groups: anti-inflammatory, analgesic, and antipyretic. The mechanisms of action have several similarities; however, they are all based on the inhibition of the COX-1 and COX-2 enzyme.

Prostaglandins play a key role in generating the inflammatory response, its biosynthesis is significantly increased in inflamed tissue, contributing to the cardinal signs of inflammation. Prostaglandins and thromboxane A2 (TXA2) are formed when arachidonic acid (released from the plasma membrane by phospholipase A2) is metabolized by the enzyme cyclooxygenase (COX-1 and COX-2).

Cyclooxygenase isoform 2 (COX-2) is a target of meloxicam. This drug is a competitive inhibitor of the active site of this enzyme, which is presented in the form of dimers. However, meloxicam binds and inactivates COX-2 at only one of the monomers, and this is sufficient to disrupt prostanoid formation.

Precautions

The following should be considered for glucosamine:

In patients with impaired glucose tolerance, glucose levels and, where appropriate, insulin requirements should be monitored prior to and periodically during treatment.

In patients with known cardiovascular risk factors, monitoring of blood lipid levels is recommended, as cases of hypercholesterolaemia have been observed in patients treated with glucosamine.

The safety and efficacy in children and young volunteers under 18 years of age have not been established, so its administration in these patients should be avoided.

The following should be considered for Meloxicam:

Arterial Hypertension: Meloxicam may cause the onset of hypertension or a worsening of pre-existing hypertension, either of which may contribute to an increased incidence of cardiovascular events. Blood pressure should be closely monitored during initiation of meloxicam treatment and during treatment. Patients taking angiotensin-converting enzyme inhibitors, thiazides, or loop diuretics may have an altered response to these therapies when taking nonsteroidal anti-inflammatory drugs (NSAIDs).

Congestive heart failure and edema: Fluid retention and edema have been observed in some patients taking meloxicam, so treatment should be monitored in patients with fluid retention, hypertension, or heart failure.

Cardiovascular Thrombotic Events: Clinical trials of various COX-2 selective and non-selective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular thrombotic events, acute myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and non-selective, may have a similar risk. Patients with known cardiovascular disease or risk factors for cardiovascular disease may be at increased risk. In patients treated with meloxicam, the potential risk of an adverse cardiovascular event is minimized by using the lowest effective dose for the shortest duration possible. Rationale for the Study

In daily practice in Mexico, the administration of drugs to patients who require a specific therapy generates a high cost regardless of whether the patient goes to a private practice or to the Public Health Sector. Interchangeable drugs are an alternative that is used in different countries including ours.

A public policy is to achieve the supply of medicines to the Mexican population, these medicines must comply with three main guiding principles: low cost, safety and efficacy; That is why it is necessary to demonstrate the safety of generic drugs with the test indicated by the General Health Council and scientifically carry out tests that demonstrate the safety of established formulations.

The "agreement that determines the type of test to demonstrate the interchangeability of generic drugs and defines the criteria that must be applied to them" published on September 19, 2017 by the General Health Council and its updates, indicates that the test designated for Glucosamine /Meloxicam Powder 1500mg/15mg is Test A, however ULTRA LABORATORIOS SA DE CV proposes to verify through a clinical study that the proposed formulation in independent doses does not cause a risky change in postprandial glucose levels in healthy research subjects.

Objectives

Comparison of postprandial glucose levels of healthy research subjects following administration of glucosamine from a 1500 mg/15 mg powdered glucosamine/meloxicam formulation prior to food intake and postprandial glucose levels of research subjects. research healthy without administration of glucosamine before food intake.

Establishment of the postprandial glucose curve in healthy volunteers during the investigation with and without the administration of glucosamine before food intake.

Statistical comparison of the postprandial curves in healthy volunteers during the investigation with and without the administration of glucosamine before food intake. statistical hypothesis

There is no significant difference in the postprandial glucose curve in healthy volunteers during the investigation with and without the administration of glucosamine before food intake.

Experimental design

This is a prospective, longitudinal study, in 2 sessions and open, with food intake. In the first session, a single dose of 1 sachet containing 1500 mg of glucosamine of the 1500mg/15mg Glucosamine/Meloxicam powder formulation is administered orally, and in the second session the aforementioned drug will not be administered, with 1 fasting period. (washing) of 10 hrs (1 day) and with 14 healthy volunteers (men and women). The study is considered research with minimal risk in accordance with the Regulations of the General Health Law of Mexico on Health Research, published in the Official Gazette of the Federation on January 6, 1987; which defines this type of research as those in which the probabilities of affecting the volunteers are significant, among which are considered: prospective studies that use risk data through common procedures in physical or psychological examinations for the diagnosis or treatment of routine, among which are considered: weighing the subject, hearing acuity tests; electrocardiogram, thermography, collection of feces and external secretions, collection of placenta during childbirth, collection of amniotic fluid when membranes rupture, saliva collection, decidual teeth and permanent teeth extracted for therapeutic indication, dental plaque and kidney stones extracted by procedure non-invasive prophylactic, non-disfiguring hair and nail trimming, blood collection by venipuncture in healthy adults, with a maximum frequency of twice a week and a maximum volume of 450 ml in two months, except during pregnancy, moderate exercise in healthy volunteers, psychological tests on people or groups in which the subject's behavior will not be manipulated, investigations with commonly used drugs, wide therapeutic margin, authorized for sale, using established indications, doses, and routes of administration and different from investigational medicinal products as defined in article 6 5 of this Regulation, among others.

Sample Size Calculations

The scope of the descriptive study is solely to verify that glucose levels are not significantly altered by the administration of Glucosamine a certain time before meals, beyond what they would increase with the meal itself, so compliance is not required. with a minimum power of 80%, and in accordance with the objective of the study, 12 volunteers are considered sufficient; 2 volunteers were added when considering the possibility of premature withdrawal or abandonment due to non-compliance with the protocol, therefore the sample size defined for the present study is 14 subjects.

Randomization and blind assignment

Randomization or blind assignment does not apply because a total of 14 volunteers will be in the two sessions, respecting Figure 1.

In the first session, the subjects will not receive any medication and will start eating according to the established schedule. In the second session, each volunteer will receive a dose of 1 sachet containing 1500 mg of glucosamine from the Glucosamine product from Ultra Laboratories, Glucosamine/Meloxicam. Powder 1500mg/15mg, you will wait a certain time and then have a breakfast rich in carbohydrates, you will start having breakfast at the same time as in the first session.

Population

Only healthy Mexican volunteers, men and women aged between 18 and 55 years old, with a body mass index between 18 and 27.00 kg/m ² .

Determining the state of health, a complete clinical history was carried out by the doctors responsible for the Clinical Investigation. In addition, the laboratory and office established by NOM-177-SSA1-2013 and NOM-012-SSA3-20123 in order to determine that these patients are not diabetic or have any glucose alteration, for which reason the glycosylated hemoglobin test and those determined by the Principal Investigator.

Treatment duration

2 sessions were held. In each session, the volunteers remained hospitalized with the Authorized Third Party for approximately 12 hours to allow standardization of the diet.

The sessions were separated by a washout time of 24 hours (1 day). Resulting in a total of 36 hours of participation for each volunteer. After the administration of the food, the sampling frequency was detailed in the Table of sampling times, number 14.

First session

A glucose tolerance curve was obtained for the 14 volunteers, after 10-12 hours of fasting and waiting the determined time for the start of food intake.

Single group: glucosamine was not ingested, a certain time was waited, food was ingested.

Washout Period: lasted 24 hours and the volunteers followed the specific instructions and stayed with the Authorized Third Party to homogenize the diet.

second session

Volunteers received Glucosamine after fasting for 10-12 hours and waited the specified time to begin food intake according to randomization performed during period 1 , with cross-allocation of medications.

Single group: 1500 mg of Glucosamine Powder was taken, a certain time was waited, and the food was ingested.

When the volunteers were discharged during session 2, they were asked directly about likely adverse events after their departure.

The clinical study was closed once the Case Report and Final Clinical Report Forms were completed.

Test Drug

All medications administered during the study were provided in accordance with the provisions of NOM-177-SSA1 -2013 AND NOM-012-SSA3-20123.

The total of the products provided was from the same batch providing a minimum quantity of:

Test drug: a total of 28 sachets.

test drug

Distinguishing Designation: NA Generic name: Glucosamine/Meloxicam Pharmaceutical form: Powder (in separate sachets)

Concentration: 1500 mg of Glucosamine/sachet Single dose of: 1 Glucosamine Sachet Manufacturer: ULTRA LABORATORIOS S.A. DE C.V.

Expiration: To be defined.

Lot: To be defined.

drug administration

The volunteers were assigned to 2 groups to facilitate their management during the administration or not of the medication, the diet and the sampling corresponding to each session, each group received or not their medication, leaving a time of 2 minutes between each session. cluster. See Table 1.

TABLE 1

In the second session that corresponds to each volunteer taking the medication, it was administered according to the pre-established sequence in the randomization table.

The Principal Investigator or the delegated physician was responsible for supervising the administration of the medication and setting the times for this process. The medication was delivered to the Clinical Staff who delivered it to the volunteers at the time indicated for its administration.

There was enough Clinical Personnel during the administration of the medication and the taking of vital signs, to avoid, as far as possible, delays in the scheduled times.

The drug was taken after at least 10-12 hours of complete fasting from food and water.

The medication was administered with 250 mL of water at room temperature, dissolving the 1500 mg powdered Glucosamine sachet with 150 mL of water and the 100 mL of water and the remainder was used to rinse the glass, ingesting the residue that remained in the same. The Clinical and Quality Assurance Staff verified that the medication was ingested and that all the water was drunk at one time. Subsequently, the volunteer's mouth was checked with a reflector lamp and tongue depressors to ensure that the tongue was consumed.

After the determined time of ingestion or non-ingestion of medication, the specified foods were consumed.

The volunteers had 30 minutes to consume all of the food, which was an exclusion criterion if the volunteer was unable to consume all of their food.

The distribution and administration of medicines were verified by Assurance of

Quality. The sequence of dosing and non-dosing was maintained, as well as the taking of blood samples from the subjects, so that the times for these activities were equivalent. medication management

The Clinical Unit was responsible for the dispensing and administration, in accordance with the procedures for this purpose.

The distribution of the test drug was carried out by the Sub-Investigator Physician or the Head of Nursing delegated by the Principal Investigator according to the distribution in the second session.

The medications were placed in plastic cups previously identified with the following data:

• Study code.

• Volunteer number.

• Name of the drug.

• Second session.

•Date.

The Clinical Unit provided the medications.

Test drug: a total of 14 glucosamine sachets with 1500 mg powder + 1 rescue sachet.

The medicine that was not used was kept in the place designated by the authorized third party, as a retention sample and these were stored, inventoried and verified in accordance with their current procedures and the conditions indicated on the product label, maintaining control of the records. reception, administration, balance and environmental storage conditions of the study drugs. Medications were stored in accordance with the times established in NOM-177-SSA1-2013 and NOM-012-SSA3-2012. Once the storage time was over, they were disposed of in accordance with the provisions of the same Standard or what its procedures indicate.

Test drugs were recorded in the Drug Retention Register and identified accordingly.

Laboratory and cabinet studies

The laboratory and cabinet tests that were evaluated for the inclusion of the volunteers in the study were:

• Hematology: hemoglobin, hematocrit, total white blood cell count with differential, and platelet count.

• Glycosylated hemoglobin test.

• Blood chemistry with glucose, urea, BUN, creatinine, uric acid.

• Liver function tests: total, direct and indirect bilirubin, total blood proteins, albumin, globulins, glutamic oxaloacetic transaminase, glutamic-pyruvic transaminase, serum alkaline phosphatase.

• Lipidic profile.

• Markers for hepatitis B and C.

• HIV test.

• General urine test.

• Electrocardiogram.

• Test for syphilis.

• Drug abuse screening test at the beginning of each period, which detects the following substances: cocaine, amphetamines, methamphetamines, tetrahydrocannabinol, benzodiazepines, and opiates during pre-screening and at the beginning of each period.

• Breathalyzer, anti-doping and pregnancy test during pre-selection and at the beginning of each period.

Volunteers with any clinically significant abnormality in the laboratory and laboratory studies were excluded, considering the general clinical condition of the volunteer and the relevant aspects of the laboratory results that determined whether or not they were consistent with the clinical evaluation.

Type of biological fluid obtained

The samples were obtained by extraction of the previously placed venous catheter, obtaining a maximum of 12 mL of blood, approximately per sample, 6 samples were obtained per volunteer per session, a maximum total of 72 mL per volunteer, approximately per session, maximum 144 mL total. Since this study consisted of 2 sessions, the samples were obtained in vacuum tubes with anticoagulant. See Table 2

Table 2

Sampling continued according to plan; however, the tolerance in the sampling lag was not considered.

Biological samples

Once the sample is obtained, the tube is shaken and placed in a rack. Once all the tubes are in place, they are transferred for processing. Plasma was obtained by centrifugation at 3500 rpm for 10 minutes at room temperature according to the Authorized Third Party procedure.

The plasma sample was placed in two cryovials according to the procedures of the Authorized Third Party. The cryovials were placed in previously registered Styrofoam racks and stored in a deep freezer at a temperature of -70 °C ± 20 °C, until they were transferred to the Analytical Unit.

Reception of samples by the analytical unit

Once the samples corresponding to the 2 sessions are in the deep freezer at -70 °C ± 20 °C, the Analytical Coordinator requests the transfer of the samples to the Analytical Unit and for their delivery the acceptance or rejection criteria were considered. , in accordance with the procedures of the Analytical Unit. The cryovials were distributed in previously labeled boxes to be transferred in coolers, to maintain the integrity of the samples and prevent the samples from being lost or confused.

Vital signs

Vital signs were taken during the evolution of the clinical study, according to the following times:

Upon admission (day before sampling): 4:00 p.m. - 7:30 p.m. (TA, FC, FR, temperature).

At the time of sample 1: <08:00 hours (TA, HR, FR, temperature).

At Tmax of the drug: around 09:30 hours (TA, HR, RF, temperature).

After Tmax of the drug: about 11:00 hours (TA, HR).

Before the end of the test: around 12:30 p.m. (TA, FC, FR, temperature).

The taking of vital signs that interferes with the taking of a sample was carried out around the established times since priority was given to obtaining the sample. If necessary, vital signs were taken according to medical indications as many times as necessary.

Diet

Análisis nutricional

The menu and feeding times were the same for all study sessions, as follows:

nutritional analysis

Development of the Study

The clinical phase of the study was carried out in accordance with the provisions of NOM-177-SSA1-2013 and NOM-012-SSA3-20123 and Good Clinical Practices.

From the beginning of the call for volunteers until the day of admission, the first session calls for the volunteers to go to the Authorized Third Party for the Informed Consent process, in which the volunteer reads, understands and signs the Informed Consent, a Contract of Confidentiality, the Internal Regulations for Volunteering, the Consent to carry out anti-doping tests and a non-pregnancy commitment letter. The days of the study were established in the Informed Consent; It also contains information on the methodology, recommendations on general measures both prior to the study and during the washout period, adverse effects of the drug under study, and the amount of remuneration.

Once the volunteer has agreed to participate in the study, they are scheduled to go to the Authorized Third Party on the day of admission to enter the study. Healthy volunteers entered the Clinical Unit, being admitted around 4:00 p.m. and 7:30 p.m. on the indicated day, and were registered in the corresponding forms. Once they entered, they were identified with a number in accordance with the protocol and their vital signs and somatometry were verified, an admission consultation was carried out, they were also asked to submit a urine sample for anti-doping tests and rapid detection of human chorionic gonadotropin in urine (in the case of women) and breathalyzer.

Subsequently, they were given dinner at 8:00 p.m. and asked to sleep around 10:30 p.m. The next morning, they get up around 06:30 a.m. to do their personal hygiene and are asked to be in the admission room at 07:00 am to start channeling. Each volunteer had a catheter placed in one of the arm veins; the catheter was new and sterile, made of flexible material and its function was to allow blood samples to be taken at different times, without the need to puncture the veins on several occasions, with the consequent pain and physical damage that can be caused. These blood samples were collected in order to be able to quantify the amount of glucose in plasma, according to the sampling scheme.

After channeling, the pre-dose sample was taken. At 8:15 am the food was delivered and they were asked to consume it in its entirety in 30 minutes, after which the food consumed was recorded.

At 08:45 a.m., a blood sample was taken at each of the times established in the Table of Sampling Times.

At various times during the study, the volunteers were checked for vital signs and asked about any discomfort they might have.

During their stay in the clinic, they were provided with food, which is programmed according to the diet of this protocol.

Sessions were separated by a 24-h washout period.

After lunch, they were asked directly about likely adverse events and asked to remain in the clinic for the start of the second session.

The second session began with the intake of dinner from 8:00 p.m. It was not necessary to perform tests again to corroborate its inclusion because the volunteers remained in the clinic throughout the study.

After dinner, they were asked to go to sleep around 10:30 p.m. The next morning they get up around 06:30 am. m. to do their personal hygiene and are asked to be in the admission room at 07:00 a.m. m. to start channeling.

After channeling, the pre-dose sample was taken. At 08:00 hours the test drug was administered. At 8:15 am the food was provided and they were asked to consume it in its entirety in 30 minutes, after which the food consumed was recorded.

At 08:45 a.m., a blood sample was taken at each of the times established in the Sampling Schedule Table of this protocol.

After the last intake of the 2nd session, they were asked directly about the probable adverse events after their discharge.

No other medication was taken during the duration of the study unless it was necessary in the presence of adverse events or reactions and authorized by the Principal Investigator or the person delegated by him, this must be duly documented. Selection of subjects

Volunteers previously recruited in the Database of Authorized Third Parties were summoned. The participation of the subjects was voluntary in accordance with the guidelines proposed in the Regulation of the General Health Law in Research Matters and their informed consent was obtained in accordance with the Law. Likewise, the standards set by the Declaration of Helsinki were maintained. and Good Clinical Practices, taking as reference NOM-177-SSA1-2013 AND NOM-012-SSA3-20123. • Only healthy Mexican volunteers between the ages of 18 and 55 years were included. To determine the state of health, a complete clinical history was carried out by the doctors responsible for the Clinical Investigation in the Authorized Third Party. In addition, the laboratory and cabinet studies marked by NOM-177-SSA1-2013 and NOM-012-SSA3-20123 and those determined by the Principal Investigator were carried out.

• Men and women were included.

• Subjects' body mass index must be between 18.0 and 27.0 kg/m ² .

• Volunteers whose Glycosylated Hemoglobin is within normal parameters were included to determine that it is not a patient with an alteration in glycemia.

The limits of variation allowed within normality at the screening visit were blood pressure between 90 and 129 mmHg systolic and between 60 and 84 mmHg diastolic, heart rate between 50 and 100 beats per minute, axillary temperature between 36.0 and 37.5 °C, and respiratory rate between 12 and 22 breaths per minute, or as determined by the procedures of the Authorized Third Party.

Exclusion criteria

The exclusion criteria given to the test drug-product are:

Hypersensitivity to glucosamine, including angioedema induced by the drug or any of the excipients.

History of orthostatic hypotension.

Severe liver failure.

Glucose resistance, or any metabolic disorder.

To safeguard the safety of the participating volunteers, the following criteria mentioned below were considered, in accordance with NOM-177-SSA1 -2013 and NOM-012-SSA3-20123:

Subjects with some clinically significant abnormality in the physical examination, in laboratory and laboratory studies, vital signs, taking into account the general health status of the volunteer and relevant aspects of the laboratory results that determine whether or not they agree with clinical evaluation. .

Subjects who have donated blood up to 8 weeks before the start of the study.

Subjects who have been exposed to drugs known to be hepatic enzyme inducers or inhibitors or who have taken potentially toxic drugs in the 30 days prior to the start of the study.

Subjects who have been hospitalized for any problem during the 4 months prior to the start of the study.

Subjects who have received investigational drugs within 90 days prior to the study. Subjects who have consumed any medication 24 hours before the start of the study, including over-the-counter medications, natural supplements, multivitamins, etc.

Subjects who have received a depot injection or implant of any drug 3 months prior to the start of the study.

Subjects who have ingested alcohol or tobacco 24 hours before the start of the study.

Subjects who have consumed coffee or beverages containing xanthines, such as caffeine, theobromine, and theophylline (tea, chocolate, cola), grapefruit and/or grape juice or extract, hibiscus water, or charcoal-broiled food 10 hours prior to start of the study.

Subjects with a history of drug abuse and/or alcoholism.

Subjects who, at the time of admission, tested positive for drug screening, rapid human chorionic gonadotropin test, and/or alcohol test.

Subjects who are found to have any alteration in their vital signs recorded in the selection of volunteers and who, in the opinion of the medical staff, put them at risk in the protocol.

Subjects with a history of cardiovascular, renal, hepatic, metabolic, gastrointestinal diseases, such as acid-peptic disease or gastrointestinal bleeding; neurological such as epilepsy, endocrine, hematopoietic, asthma, mental illness or other organic abnormalities.

Subjects with any food allergy, intolerance restriction or special diet, which in the opinion of the Principal Investigator or delegated Sub-Investigator Physician may exclude the subject's participation in the study.

Subjects with unwillingness or inability to comply with the lifestyle measures described above.

Subjects with intolerance to venipuncture.

Subjects with mental disabilities for decision making.

Safeguard variables

The subjects reported any symptoms that they present to the Clinical Staff in charge of carrying out the study, likewise the medical staff conducted a directed questioning at each of the moments of the intake on any symptom that the volunteer presents after the administration of the medication and in case exhibition, they were recorded in the Case Record and in the corresponding registry of adverse events.

A severe hypersensitivity reaction (anaphylactic reaction), shock, severe hepatotoxicity or others that endanger the life or integrity of the subject were considered emergency situations. For this reason and according to the severity of the adverse effects that may occur in the other volunteers, the study may be suspended at any time by decision of the Principal Investigator to the Research Ethics Committee and the Research Committee. Adverse events

Definition: Any undesirable medical event that may occur in a test subject during the clinical investigation phase of a drug or vaccine but that is not necessarily causally related to the drug or vaccine. The adverse event does not necessarily have to have a causal relationship with said treatment. Thus, an adverse event can be any unintentional unfavorable sign (including abnormal laboratory result), symptom, or condition that is temporarily associated with the use of the (investigational) medicinal product, whether or not related to the (investigational) medicinal product.

The classification of adverse events according to their severity of clinical manifestation, according to NOM-220-SSA1 -2016 for the Installation and operation of pharmacovigilance, is as follows:

Mild: they present with signs and symptoms that are easily tolerated, do not require treatment or prolong hospitalization, and may or may not require discontinuation of the medication.

Moderate: interfere with normal activities, without directly threatening the life of the patient. It requires pharmacological treatment and may or may not require the suspension of the drug causing the adverse reaction.

Serious: interfere with normal activities (and can cause sick leave or school leave). It requires pharmacological treatment and suspension of the drug causing the event, reaction or suspected reaction.

Depending on the result, they are classified according to the severity of the clinical manifestation into:

Severe (severe): Any clinically important manifestation that occurs with the administration of any dose of a drug, and that:

Cause the death of the patient.

Endangers the life or causes the death of the patient at the time they occur.

They force hospitalization or prolong hospital stay.

They are the cause of persistent or serious invalidity or incapacity.

It is the cause of alterations or malformations in the newborn.

Non-serious: Adverse events that do not meet the severity criteria listed above.

Assessment of causality:

True: a clinical event, including abnormalities in laboratory tests, manifesting with a plausible time sequence in relation to drug administration, and that cannot be explained by the concurrent disease, nor by other drugs or substances. The response to drug withdrawal (withdrawal) must be clinically plausible. The event must be definitive from the pharmacological or phenomenological point of view, using, if necessary, a conclusive rechallenge procedure.

Probable: A clinical event, including laboratory test abnormalities, that is manifests itself in a reasonable time sequence relative to drug administration, is unlikely to be attributable to concurrent disease or other drugs or substances, and that when the drug is withdrawn, a clinically reasonable response occurs. Information on rechallenge is not required to assign this definition.

Possible: A clinical event, including abnormalities in laboratory tests, manifesting with a reasonable time sequence in relation to drug administration, but which can also be explained by concurrent disease, or by other drugs or substances. Information about drug recall may be missing or unclear.

Unlikely: clinical event, including abnormalities in laboratory tests, manifesting with an improbable time sequence in relation to drug administration, and that can be more plausibly explained by the concurrent disease, or by other drugs or substances.

Conditional/Unclassified: A clinical event, including laboratory test abnormalities, reported as an adverse reaction, for which more data is required for proper evaluation, or additional data is being reviewed.

Not evaluable/Unclassified: notification that suggests an adverse reaction, but that cannot be judged because the information is insufficient or contradictory, and that cannot be verified or completed in its data.

The subjects reported any symptoms that they present to the medical, nursing or clinical staff in charge of carrying out the study, likewise a directed questioning was carried out at each of the moments of the shots about any symptoms that the volunteer presents after the administration of the medication and if present, it was recorded in the Case Report Format and in the corresponding adverse event registry.

This description includes the nature of the signs and symptoms, the date and time they occurred, the severity, whether or not treatment was needed, whether or not the effects are attributable to the drug, and the date and time of their resolution.

For the management and reporting of adverse events during the bioequivalence study, the provisions of NOM-220-SSA1-201618 are followed. Any serious adverse event must be reported immediately to the Health Manager of the Clinical Unit who reports to the Health Authority and the Research Ethics Committee and the Research Committee, and to the sponsor. Any serious adverse event was reported to the National Center for Pharmacovigilance within a period not exceeding 7 business days after its identification; non-serious events were included in the Final Clinical Report of the study.

Adverse Event Notification Directory. Sponsor/Head of Pharmacovigilance: Dr. Cristina Desirée Morales Rodríguez; Tel: (01 33) 35872370 Ext 1445; Email: moralesc@ultralaboratorios.com. max; Authorized Third Party Research Committee: Research Ethics Committee: Principal Investigator: Withdrawal of volunteers from the study

Presence of signs and symptoms that suggest a critical condition for the volunteer.

Moderate or severe adverse reaction due to study drug.

Presence of vomiting or diarrhea at any time during the therapeutic dosing interval.

Volunteers with difficulty swallowing study drug.

If any of the participating volunteers ingest alcoholic beverages or ingest drugs that modify the pharmacokinetics of the drug in question, 24 hours before the period, it will be sufficient reason to be withdrawn from the study.

Non-compliance with study procedures.

Withdrawal of informed consent.

Positive result of the breathalyzer and/or anti-doping test.

Volunteers were withdrawn from the study for protocol violations or in the opinion of the Principal Investigator for medical reasons (adverse events). Volunteers withdrawn from the study were not replaced. Any volunteer could stop participating in the study, at any time they decided.

All the data and samples for bioavailability, if any, of the volunteer or volunteers that were withdrawn, were sent to the Analytical Unit with notification to the Analytical, Biostatistics and Quality Coordinators, indicating the date and reason for which they were withdrawn. of the study, in the Clinical Case Form and in the Final Clinical Report.

The samples of the volunteers excluded from the study may be analyzed or not, considering what is established with the aforementioned criteria.

study suspension

In the event of any major deviation or administrative situation that jeopardized the viability of the study, the Principal Investigator made a joint decision with the Clinical, Analytical, Biostatistical, and Quality Coordinators and the General Directorate and notified the Research Ethics Committee and the Research Committee of the Authorized Third Party and the Sanitary Managers on the need to cancel the study in any of its phases. For example:

Meteorological causes of force majeure (hurricane, flood, extreme cold, etc.)

Unit Infrastructure Failure.

Various administrative situations.

Others.

A temporary suspension could be made to analyze the causes in 48 hours and the resumption or definitive suspension would be determined.

Statistic analysis

In accordance with numeral 8.5.5 of NOM-177-SSA1-2013, all treated research volunteers were included in the statistical analysis; however, volunteers who they did not complete the study and dropped out, at any stage they were not included in the statistical analysis. From the plasma levels determined in each session, plasma concentration profiles versus time were plotted for each research volunteer in their initial state with food and with medication administration subsequently accompanied by food.

It was determined if there was a significant difference in the plasmatic concentration values for each sampling time.

All of the above was evaluated using the Minitab software to assess whether or not there is a significant difference between both states of the subject using the Student's t hypothesis test, with a significance level of 0.05, for the plasma concentration parameters at each hour.

test hypothesis

For log transformed data:

H01 : Glucose levels after consuming food are proportional without the consumption of Glucosamine or when Glucosamine is consumed with a certain time before meals.

H02: Glucose levels after consuming food are not proportional without Glucosamine consumption or when Glucosamine is consumed with a certain time before meals.

Statistical analysis plan

It was determined by the Authorized Third Party.

If a research volunteer has been eliminated, according to the samples of the excluded research volunteers will be analyzed and their results will be presented. Likewise, the statistical analysis will be carried out with and without the eliminated research volunteers and both results will be presented.

Analytical methodology

Plasma glucose was quantified with a validated method according to authorized third-party procedures.

Quality assurance in the clinical process

Quality assurance was carried out with the monitoring and verification of the studies to ensure the quality of the clinical processes before, during and after the study, as well as the critical points of the processes, documents and records that must comply with NOM-177. - SSA1-2013 and NOM-012-SSA3-2012, Good Clinical Practices and other applicable regulations.

Deviations from the protocol and the statistical plan were described in the corresponding Final Quality Assurance Report.

Management of confidentiality of study information

The information obtained in this study was exchanged and treated confidentially by the Authorized Third Party and the sponsor. The data was used by the parties involved after consultation and mutual agreement. The Ministry of Health, COFEPRIS, as well as the Research Ethics Committee and the Research Committee and the sponsor reviewed the documentation generated during this study at all times.

For the handling of voluntary information, the provisions of the Federal Law on Protection of Personal Data Held by Private Parties were considered.

This protocol was approved by the Research Ethics Committee and the Research Committee to verify the feasibility and adherence of the study to what is established by current regulations before its execution. Likewise, it was presented for authorization to the Sanitary Authorization Commission, in accordance with the powers of the Federal Commission for Protection against Sanitary Risks (COFEPRIS) in accordance with NOM-177-SSA1-2013 and NOM-012-SSA3 -2012.

The study volunteers were informed through the Informed Consent of everything related to the study, doubts were clarified and their written consent was issued. The Informed Consent specified that the sponsor undertook to pay for the immediate treatment derived from accidents or illnesses caused by their participation in the study until their resolution according to medical criteria. The sponsor did not pay anything for willful negligence, irresponsible behavior, or medical conditions unrelated to the study. Volunteers who participated in the study received financial compensation at the end of the study.

Deviation from what is established in the protocol:

When a deviation from what was established in the protocol for a volunteer occurred, the Principal Investigator, at his discretion, communicated with the Health Manager of the Clinical and Analytical Units, the Research Ethics Committee and the Research Committee, and the monitor of the study. When necessary, the Research Ethics Committee and the Research Committee were able to perform an internal audit of the study. Each deviation when reported was verified and documented for each volunteer.

Modifications to the research protocol:

Medical modifications were made with the consent of the Principal Investigator of the study site and were properly documented and reported. Documentation annexed to the protocol

Case report format and instructions for filling it out.

Informed consent.

Non-pregnancy commitment letter.

Letter of approval from the DEBBIOM Research Ethics Committee.

Letter of approval from the DEBBIOM Research Committee.

Flowchart. Drug-product monograph.

EXAMPLE 2. Calorimetry study to determine Glucosamine/Meloxicam compatibility

Glucosamine is a natural aminomonosaccharide, an endogenous molecule, a normal constituent of the polysaccharide chain of the cartilage matrix and of the glycosaminoglycans of the synovial fluid.

Meloxicam (MLX) is a non-steroidal anti-inflammatory drug (NSAID) of the Oxicam family. This group of NSAIDs is frequently used in the treatment of rheumatoid arthritis and postoperative inflammation.

In this example, the results obtained in the Glucosamine/Meloxicam compatibility study were evaluated, using the differential scanning calorimetry (DSC) technique. This technique is based on thermodynamic changes, that is, measuring the difference in absorbed heat flows. or emitted by the sample along a temperature gradient. To carry out these determinations, it is necessary to first characterize the individual transitions of each compound separately and then analyze the mixture thereof, to determine if their melting points and/or their characteristic transitions are altered.

In this regard, the melting points of each active principle are:

Glucosamine: 192.0 °C

Meloxicam: 255.0 °C

equipment calibration

The equipment prior to its use was calibrated with materials whose melting points and enthalpy values at certain conditions are standardized, in this case Indium (In) and Zinc (Zn) are used as reference substances.

Figures 2A and 2B show the thermograms of the evaluation of Glucosamine (A) and Meloxicam (B) as raw material.

Figure 3 shows the thermogram of the evaluation of the Glucosamine-Meloxicam mixture. Results

individual components

Con base en los resultados obtenidos durante el Desarrollo del producto en la etapa de Investigación de compatibilidad de los componentes de la formulación, utilizando la técnica analítica de DSC, se demostró la interacción Glucosamina/Meloxicam, cuando estos están mezclados entre sí, es decir se produce un cambio de entalpia, provocado por un cambio en sus puntos de fusión tanto de PA Glucosamina como del PA de Meloxicam, obteniendo en este último dos transiciones que no se observan en el termograma individual, razón principal por la cual el desarrollo del medicamento se lleva a cabo en sobres distintos, logrando así asegurar la estabilidad de ambos activos. Glucosamine-Meloxicam mixture

Based on the results obtained during the Development of the product in the Investigation stage of the compatibility of the formulation components, using the DSC analytical technique, the Glucosamine/Meloxicam interaction was demonstrated, when these are mixed together, that is, they are produces an enthalpy change, caused by a change in their melting points of both Glucosamine PA and Meloxicam PA, obtaining in the latter two transitions that are not observed in the individual thermogram, the main reason why the development of the drug is carried out in different envelopes, thus ensuring the stability of both assets.

The scope of the present invention is not intended to be limited by the specific descriptions of preferred implementations in this section or elsewhere in this specification, and may be defined by the claims as presented in this section or elsewhere in this specification or as it appears in the future. The language of the claims is to be construed broadly based on the language used in the claims and not limited to the examples described herein or during the filing of the application, which examples are to be construed as non-exclusive.

Claims

1. A kit comprising: A. a first independent pharmaceutical composition comprising at least one active ingredient, B. a second independent pharmaceutical composition comprising at least a second active ingredient, C. wherein said at least first and second independent compositions are arranged in a suitable container that is configured to be ingested independently by a subject during scheduled dosing periods of the day; Y D. wherein said at least two independent pharmaceutical compositions are not in contact with each other. 2. The kit of claim 1, wherein the container is selected from the group consisting of envelopes, plastic containers, bags and/or sacks. 3. A kit comprising: A. a first independent composition that includes an effective amount of glucosamine, and B. a second independent composition that includes an effective amount of meloxicam; C. wherein said at least first and second independent compositions are arranged in a suitable container that is configured to be ingested independently by a subject during scheduled dosing periods of the day; Y D. wherein said at least two independent pharmaceutical compositions are not in contact with each other. The kit of claim 3, for use in the treatment of degenerative osteoarticular disease, wherein the kit is adapted to be administrable to a subject in need thereof. The kit of claim 4, wherein said kit comprising glucosamine and meloxicam is adapted to be administrable before and after food intake, respectively, to prevent both glucose rise and gastrointestinal damage.