DESC:Title of the invention-
Yohimbine Formulations

Field of the Invention
The present embodiments are directed to novel formulations of Yohimbine/ Alpha-Yohimbine, including sustained-release formulations.

Background

Yohimbine is an indole alkaloid derived from the bark of the Pausinystalia yohimbe tree. Yohimbine is also an aphrodisiac and can aid erectile dysfunction. It is also a general stimulant and used for condition of dry mouth. It has also been used in studies investigating autonomic failure and orthostatic hypotension.
Yohimbine has high affinity for the a2-adrenergic receptor, moderate affinity for the a1 receptor, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2B, and D2 receptors, and weak affinity for the 5-HT1E, 5-HT2A, 5-HT5A, 5-HT7, and D3 receptors. It behaves as an antagonistat a1-adrenergic, a2-adrenergic, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, and D2, and as a partial agonist at 5-HT1A.Yohimbine interacts with serotonin and dopamine receptors in high concentrations.

Yohimbine drug available commercially in tablet and capsule forms designed for oral administration of one to four tablets aws per requirement per day. Yohimbine 6 mg given 3 times a day has been used in xerostomia. A mean dose of 0.4 mg/kg body weight or 30 mg daily, and a maximum of 50 mg, has been used in erectile dysfunction cases. Dosages of 0.2mg/kg bodyweight have been successfully used to increase fat burning without significant implications on cardiovascular parameters like heart rate and blood pressure. This results in a dosage of: 14 mg for a 150lb person, 18 mg for a 200lb person, and 22 mg for a 250lb person.
Yohimbine HCl has a very short half-life of only around 1 – 1.5 hours. This means that after around 3 hours its effects should have worn off entirely. The length of the effects depends on metabolism of individual.

Summary of Invention
In an embodiment, a pharmaceutical formulation comprises controlled- release Yohimbine/ Alpha-Yohimbine. In some embodiments the controlled-release Yohimbine/ Alpha-Yohimbine comprises sustained-release Yohimbine/ Alpha-Yohimbine. In some embodiments the pharmaceutical formulation comprises one of more retardant excipients. In some embodiments the retardant excipient is configured to modify the dissolution profile of the sustained-release Yohimbine/ Alpha-Yohimbine.

Description of Invention

Hence further wherever Yohimbine mentioned should be considers as Salt, ester, isomer, enantiomer polymorph, cocrystal or/and Premix of Yohimbine.
Yohimbine can be considered as Alpha-Yohimbine for the rest of Description..

Various embodiments provide pharmaceutical formulations that comprise controlled-release Yohimbine. Such formulations can be configured in various ways and in a variety of dosage forms, such as tablets and beads, to modify the release of the Yohimbine. For example, one type of controlled-release Yohimbine pharmaceutical formulation is a sustained-release Yohimbine pharmaceutical formulation. Sustained- release Yohimbine pharmaceutical formulations can contain a variety of excipients, such as retardant excipients (also referred to as release modifiers) and/or fillers that are selected and incorporated into the formulation in such a way as to slow the dissolution rate of the formulation (and thereby slow the dissolution and/or release of the Yohimbine) under in vivo conditions as compared to an otherwise comparable immediate-release formulation. Thus, a "comparable" immediate-release formulation is one that is substantially identical to the controlled-release formulation, except that that it is configured to provide immediate-release instead of controlled-release under substantially identical conditions.

The term "immediate-release" is used herein to specify a formulation that is not configured to alter the dissolution profile of the active ingredient (e.g., Yohimbine). For example, an immediate-release pharmaceutical formulation may be a pharmaceutical formulation that does not contain ingredients that have been included for the purpose o'f altering the dissolution profile. An immediate-release formulation thus includes drug formulations that take less than 60 minutes for substantially complete dissolution of the drug in a standard dissolution test. Standard dissolution test comprises based on requirement of drug release and based on design of dosage form. Dissolution test also based on Solubility of Yohimbine and Alpha-Yohimbine and requiremt of release pattern and physicochemical properties of dosage form. The term "controlled-release" is used herein in its ordinary sense and thus includes pharmaceutical formulations that are combined with ingredients to alter their dissolution profile. A "sustained-release" formulation is a type of controlled-release formulation, wherein ingredients have been added to a pharmaceutical formulation such that the dissolution profile of the active ingredient is extended over a longer period of time than that of an otherwise comparable immediate- release formulation. A controlled-release formulation thus includes drug formulations that take 60 minutes or longer for substantially complete dissolution of the drug in a standard dissolution test, conditions which are representative of the in vivo release profile.

The term "orally deliverable" is used herein in its ordinary sense and thus includes drug formulations suitable for oral, including peroral and intra-oral (e.g., sublingual or buccal) administration. Preferred compositions are adapted primarily for peroral administration, e.g., for swallowing. Examples of preferred orally deliverable compositions include discrete solid articles such as tablets, pellets, granules and capsules, which are typically swallowed whole or broken, with the aid of water or other drinkable fluid.

The term "therapeutically effective amount" is used herein in its ordinary sense and thus includes daily dosage amounts of a drug or drug combination that, when administered as part of a regimen, provides therapeutic benefit in the treatment of a condition or disorder for which the drug or drug combination is indicated. For example, in some preferred embodiments, amounts per dose of Yohimbine are likely to be found in a range from about 0.1 mg to about 50 mg, in more preferred embodiments amounts per dose are found in a range of about 0.2 mg to about 30 mg.

The term "pharmaceutically acceptable salt" is used herein in its ordinary sense and thus includes a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the present disclosure with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound of the present disclosure with a base to form a salt such as ammonium salt, an alkali metal salt such as a sodium or a potassium salt, an alkaline earth metal salt such as a calcium or a magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl) methylamine and salts thereof with amino acids such as arginine, lysine and the like. Unless the context dictates otherwise, reference herein to a particular compound will be understood to include such salt forms.

In the context of the present disclosure, by "about" a certain amount it is meant that the amount is within ±20% of the stated amount, or preferably within ±10% of the stated amount, or more preferably within ± 5% of the stated amount. Thus, for example, reference to a formulation that comprises "about 70% Yohimbine by weight" will be understood as a reference to an amount of Yohimbine in the pharmaceutical formulation that is 70% ± 14% (i.e., between 56% and 84%) by weight, or preferably 70% ± 7% (i.e., between 63% and 77% by weight), or more preferably 70% ± 4% (i.e., between 66% and 74% by weight)."some embodiments, the sustained-release Yohimbine pharmaceutical formulation comprises one or more retardant excipients. In this context, the term "retardant" excipient is used herein in its ordinary sense and thus includes an excipient that is configured (e.g., incorporated into the formulation) in such a way as to control a dissolution profile of the drug, e.g., slow the dissolution of the Yohimbine in a standard dissolution test, as compared to an otherwise comparable pharmaceutical formulation that does not contain the retardant excipient. Examples of pharmaceutically acceptable retardant excipients include hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose (HPC), methylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, microcrystalline cellulose, corn starch, polyethylene oxide, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl acetate phthalate, polyethylene glycol, zein, poly-DL-lactide-co-glycolide, dicalcium phosphate, calcium sulfate, and mixtures thereof. In some embodiments the retardant excipient comprises a sustained-release polymer, e.g., at least one of hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose (HPC), methylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, microcrystalline cellulose, corn starch, polyethylene oxide, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl acetate phthalate, polyethylene glycol, zein, poly-DL-lactide-co-glycolide, and mixtures thereof. Retardant excipients may be referred to herein as release modifiers.

The term in vivo "absorption" is used herein in its ordinary sense and thus includes reference to the percentage of Yohimbine that enters the bloodstream, as conventionally calculated from data of a standard pharmacokinetic (PK) study involving oral administration of a single dose of Yohimbine. It will be understood that PK data are subject to the usual variation seen in biological data, thus the absorption percentages specified herein are means from a population, typically at least about 20 in number, of individual healthy adults in accordance with standard statistical practice

The sustained-release Yohimbine pharmaceutical formulation comprises one or more retardant excipients. In this context, the term "retardant" excipient is used herein in its ordinary sense and thus includes an excipient that is configured (e.g., incorporated into the formulation) in such a way as to control a dissolution profile of the drug, e.g., slow the dissolution of the Yohimbine in a standard dissolution test, as compared to an otherwise comparable pharmaceutical formulation that does not contain the retardant excipient. Examples of pharmaceutically acceptable retardant excipients include hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose (HPC), methylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, microcrystalline cellulose, corn starch, polyethylene oxide, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl acetate phthalate, polyethylene glycol, zein, poly-DL-lactide-co-glycolide, dicalcium phosphate, calcium sulfate, and mixtures thereof. In some embodiments the retardant excipient comprises a sustained-release polymer, e.g., at least one of hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose (HPC), methylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, microcrystalline cellulose, corn starch, polyethylene oxide, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl acetate phthalate, polyethylene glycol, zein, poly-DL-lactide-co-glycolide, and mixtures thereof. Retardant excipients may be referred to herein as release modifiers.
Retardant excipient can be used alone or on combinaion in nay proportion with any other excipient or retardant to achieve desired dissolution profile.
There are various ways that an excipient can be configured to control a dissolution profile of a sustained-release formulation. For example, the excipient can be intimately mixed with the drug (e.g., Yohimbine) in an amount effective for controlling release of the drug from the pharmaceutical formulation. Such a mixture can be in various forms, e.g., a dry mixture, a wet mixture, beads, etc., and may be formed in various ways. The resulting mixture can then be formed into the desired dosage form, e.g., tablet or capsule. The sustained-release Yohimbine pharmaceutical formulation comprises at least about 5 weight %, preferably at least about 10 weight %, of the retardant excipient(s). Effective amounts of retardant excipient(s) for controlling release may be determined by routine experimentation informed by the guidance provided herein.
Various dissolution characteristics of the dissolution profile of the sustained-release Yohimbine pharmaceutical formulation can be controlled by appropriate configuration of the retardant excipient incorporated therein. Preferably, the dissolution profile comprises a dissolution rate that is slower than a dissolution rate of a comparable immediaterelease Yohimbine formulation. For example, in some embodiments, the pharmaceutical formulation comprises Yohimbine and at least one retardant excipient configured to control an in vitro release profile within the following ranges:

Table 1- Drug release profile
Hours % release
1 0-40
2 10-60
4 15-70
6 20-80
10 >=70

The in vitro release profile may be estimated by dissolution measurements in water at 37° C. For example, a preferred dissolution profile comprises at least one dissolution characteristic selected from:
(a)less than about 70% of Yohimbine in the sustained-release Yohimbine is dissolved within a first hour in a standard dissolution test,
(b)less than about 40% of the Yohimbine in the sustained-release Yohimbine is dissolved within a first hour in a standard dissolution test,
(c) less than about 30% of the Yohimbine in the sustained-release Yohimbine is dissolved within a first hour in a standard dissolution test,
(d) less than about 75% of the Yohimbine in the sustained-release Yohimbine is dissolved within a second hour in a standard dissolution test,
(e) less than about 55% of the Yohimbine in the sustained-release Yohimbine is dissolved within a second hour in a standard dissolution test, and
(f) less than about 35% of the Yohimbine in the sustained-release Yohimbine is dissolved within a second hour in a standard dissolution test.

In an embodiment, the sustained-release pharmaceutical formulation comprises Yohimbine and at least one retardant excipient configured to provide, upon administration to a patient, an average free serum Yohimbine Cmax value that is less than (e.g., at least about 5% less than) the average free serum Yohimbine Cmax value of a comparable immediate-release Yohimbine under comparable conditions. For example, the retardant excipient can be configured to control an in v ivo free Yohimbine serum profile wherein there is greater Yohimbine bioavailabilty, as indicted by an area under the serum concentration curve at steady state that is substantially equal to or greater than a conventional immediate-release Yohimbine formulation at the same dose, and a lower Cmax at steady state than a conventional immediate-release Yohimbine formulation at the same dose.

Sustained-release Yohimbine pharmaceutical formulation as described herein may be formulated to be useful for oral administration under dosage schedules in the range of once or twice daily to once every two to seven days, to a subject having a condition or disorder for which the administration of Yohimbine is indicated. Thus, in some embodiments a pharmaceutical formulation comprises a controlled dosage form suitable for daily or weekly administration of Yohimbine.

In an embodiment, a method of treatment comprises administering a sustained-release Yohimbine pharmaceutical formulation as described herein to a patient in need thereof. In a preferred embodiment, the patient experiences a reduced risk of an adverse event associated with administering a comparable dosage of an immediate-release Yohimbine For example, in some embodiments, a sustained-release Yohimbine pharmaceutical formulation having in vitro release and/or in vivo PK parameters as described herein is advantageous in having reduced potential to cause undesirable adverse events that may be related to a combination of high Cmax and short Tmax, in comparison with other oncedaily dosage forms (such as immediate-release forms). In some embodiments, an incidence of adverse events is no greater than with an immediate-release dosage form. More preferably, the incidence of adverse events is significantly lower than with such an immediate-release regimen. Preferably these advantages become more pronounced with increases in daily dosage during the initiation and/or course of Yohimbine therapy.

In some embodiments, the sustained-release Yohimbine pharmaceutical formulation is formed into capsules, tablets or other solid dosage forms suitable for oral administration. In preferred embodiments, the sustained-release Yohimbine pharmaceutical formulation is formulated as a discrete solid dosage unit such as a tablet or capsule, wherein the Yohimbine or salt thereof is present therein as particles, and is formulated together with one or more pharmaceutically acceptable excipients. In some embodiments the excipients are retardant excipients selected at least in part to provide a release profile and/or PK profile consistent with the desired profiles described herein.

Sustained-release Yohimbine pharmaceutical formulations can be configured in a variety of dosage forms, such as tablets and beads; can contain a variety of fillers and excipients, such as retardant excipients (also referred to a release modifiers); and may be made in a variety of ways. Those skilled in the art may determine the appropriate configuration by routine experimentation guided by the descriptions provided herein.
Sustained-release Yohimbine pharmaceutical formulations may contain fillers. Examples of suitable fillers include, but are not limited to, METHOCEL® methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), corn starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked PVP, and the like. [0034] Sustained-release Yohimbine pharmaceutical formulations may contain excipients. Examples of suitable excipients include, but are not limited to, acetyltriethyl citrate (ATEC), acetyltri-n-butyl citrate (ATBC), aspartame, lactose, alginates, calcium carbonate, carbopol, carrageenan, cellulose, cellulose acetate phthalate, croscarmellose sodium, crospovidone, dextrose, dibutyl sebacate, ethylcellulose, fructose, gellan gum, glyceryl behenate, guar gum, lactose, lauryl lactate, low-substituted hydroxypryopl cellulose (L-HPC), magnesium stearate, maltodextrin, maltose, mannitol, methylcellulose, microcrystalline cellulose, methacrylate, sodium carboxymethylcellulose, polyvinyl acetate phthalate (PVAP), povidone, shellac, sodium starch glycolate, sorbitol, starch, sucrose, triacetin, triethylcitrate, vegetable based fatty acid, xanthan gum, xylitol, and the like.

In preferred embodiments, the sustained-release Yohimbine pharmaceutical formulation comprises Yohimbine, methylcellulose and microcrystalline cellulose. In some embodiments, the formulation comprises, for example, from about 30%, 40%, or 50%, to about 80% or 90% Yohimbine by weight. In some embodiments, the formulation comprises about 0.1%, 0.5%, 1%, 3%, 5%, 10% or 20% Yohimbine by weight. Preferably, the Yohimbine is present at a percentage of about 55%, 60%, 65%, or 70% by weight. In other preferred embodiments, the formulation comprises about 95% Yohimbine.

In some embodiments the dissolution rate of the formulation can be decreased by adding components that make the formulation more hydrophobic. For example, addition of polymers such as ethylcelluloses, wax, magnesium stearate, and the like decreases the dissolution rate.

In some embodiments, the dissolution rate of the sustained-release Yohimbine pharmaceutical formulation is such that about 25% of the Yohimbine in the dosage form is dissolved within the first hour, about 60% of the Yohimbine is dissolved within the first 6 hours, about 80% of the Yohimbine is dissolved within the first 9 hours, and substantially all of the Yohimbine is dissolved within the first 12 hours. In other embodiments, the dissolution rate of the sustained-release Yohimbine pharmaceutical formulation is such that about 35% of the Yohimbine in the dosage form is dissolved within the first hour, about 85% of the Yohimbine is dissolved within the first 6 hours, and substantially all of the Yohimbine is dissolved within the first 9 hours. In yet other embodiments, the dissolution rate of the sustained-release Yohimbine pharmaceutical formulation in the dosage form is such that about 45% of the Yohimbine in the beads is dissolved within the first hour, and substantially all of the Yohimbine is dissolved within the first 6 hours.

The dissolution rate of the formulation can also be slowed by coating the dosage form. Examples of coatings include enteric coatings, sustained-release polymers, and the like.
The sustained-release Yohimbine pharmaceutical formulation can take about, for example, from 2, 4, 6, or 8 hours to about 15, 20, or 25 hours to dissolve. Preferably, the formulation has a dissolution rate of from about 3, 4, 5, or 6 to about 8, 9, or 10 hours.

Another embodiment provides a method of preparing sustained-release Yohimbine pharmaceutical formulation. The method comprises mixing Yohimbine with an excipient and/or filler to form a mixture, and forming a suitable dosage form (e.g., tablet, bead, etc.) from the mixture. In an embodiment, the Yohimbine is mixed with the filler and/or excipient to form a wet mixture. The wet mixture can then be formed into particles or beads, which can then be dried. The dried product can then be tableted or placed into a gelatin capsule for oral delivery.

In an embodiment, the sustained-release Yohimbine pharmaceutical formulation is in the form of beads. In some embodiments, the beads comprise Yohimbine and a filler. In other embodiments, the beads further comprise an excipient. In some embodiments, the filler and/or the excipient are in polymeric form.
As used herein, "beads" can be, for example, spheres, pellets, microspheres, particles, microparticles, granules, and the like. The beads can have any desired shape. The shape can be, for example, spherical, substantially spherical, rod-like, cylindrical, oval, elliptical, granular, and the like. The size and shape of the bead can be modified, if desired, to alter dissolution rates. The beads may be coated or may be uncoated. The beads may be formed into a capsule for oral delivery, a tablet, or any other desired solid oral dosage form, with or without other ingredients.
In an embodiment, a pharmaceutical formulation comprises a bead that comprises sustained-release Yohimbine and a filler. In some embodiments the bead further comprises an excipient. In some embodiments the filler is a polymer. In some embodiments the excipient is a polymer. In some embodiments the filler is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), corn starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and cross-linked PVP. In some embodiments the excipient is selected from the group consisting of acetyltriethyl citrate (ATEC), acetyltri-n-butyl citrate (ATBC), aspartame, lactose, alginates, calcium carbonate, carbopol, carrageenan, cellulose, cellulose acetate phthalate, croscarmellose sodium, crospovidone, dextrose, dibutyl sebacate, ethylcellulose, fructose, gellan gum, glyceryl behenate, guar gum, lactose, lauryl lactate, low-substituted hydroxypropyl cellulose (L-HPC), magnesium stearate, maltodextrin, maltose, mannitol, methylcellulose, microcrystalline cellulose, methacrylate, sodium carboxymethylcellulose, polyvinyl acetate phathalate (PVAP), povidone, shellac, sodium starch glycolate, sorbitol, starch, sucrose, triacetin, triethylcitrate, vegetable based fatty acid, xanthan gum, and xylitol. In some embodiments "the bead" comprises Yohimbine, methylcellulose and microcrystalline cellulose. In some embodiments the bead comprises from about 0.1% to about 95% Yohimbine by weight. In some embodiments the bead comprises between about 3% to about 99.9% microcrystalline cellulose by weight. In some embodiments the bead comprises about 0% to about 40% methylcellulose by weight.

In some embodiments the beads can advantageously be formed from a wet mixture using any suitable apparatus. Preferably, an extrusion device is used. The wet mixture can be extruded to form "spaghetti-like" strands. These can be cut, preferably as they are being extruded, to form pellets of a desired size. The wet cylindrical pellets can, in turn, be placed into a "spheronizer" that forms them into generally spherical shapes. The spheronizer comprises a rotating plate or other rotating mechanism onto or into which the pellets are introduced and maintained for a sufficient time to generate beads of a desired spherical shape. These spheres can then be collected and dried by any suitable means. Preferably, the beads are dried using a fluid bed drying process. Other suitable means for drying the beads, as will be known by those in the art, can be used.

The spheronizer is preferably fitted with a screen having holes of a specified size, such as 16 mesh, 18 mesh, 20 mesh, 25 mesh, or other sizes. The screen causes beads of certain diameter to leave the spheronizer, thereby generating beads of relatively uniform diameter. In some embodiments, the Yohimbine bead size can range, for example, from a range of about 10, 50, or 100 µm to about 700, 900, or 1,000 µm. In other embodiments, the bead size is from about 150, 200, 250 µm, to about 300, 400, or 500 µm. In yet other embodiments, the bead size is about 200 µm. In some embodiments, the preferred bead diameter is between 0.71 mm and 1.17 mm.

The spheronizer speed also has an effect on the bead size. Faster spheronizer rotation speeds result in smaller beads. In some embodiments, the spheronizer speed is between about 1 and about 900 rpm. In further embodiments, the spheronizer speed is between about 10 and about 800 rpm.
Patient compliance with a Yohimbine treatment is much improved by administration of a sustained-release formulation that results in reaching a steady state concentration substantially equivalent to the immediate-release Yohimbine capsule, but with a lower effective dose (resulting in a lower Cmax). An important feature of a preferred sustained-release Yohimbine formulation is the more effective control of free fraction Yohimbine in serum.

In some embodiment ready to use sustained release granules can be prepared. These granules can be administered as it is or with any fluid. This ready to use suspended granules administer in due time before 1-3 hours.

Controlled release formulation can be reservior type or matrix system based. It may use osmotic drug delivery or use ion exhcnage resins for drug delivery.
Tablet formulation may be monolayer or multilayer formulation. Solid dosage form can be in capsule, tablet, pellets or granules form.

Cotrolled release formulation may be floating drug delivery, gastro-retentive drug delivery, Gastro-resistant drug delivery, Enteric coated drug delivery, extended drug delivery or colon targeted drug delivery. The selection and concentration of excipients should be based in the mode of drug delivery required.

Examples

The examples below are non-limiting and are merely representative of various embodiments of the present disclosure.

Example 1 : Formulation of SR (Sustained-Release) Yohimbine

The following formulation method is an example of the preparation of a slow-release Yohimbine formulation. The sustained-release formulation dissolves more slowly than, for example, the immediate-release formulation.. Wet granulation, extrusion, spheronization and fluid-bed drying processes were utilized to produce sustained-release Yohimbine pellets.
To prepare the wet granules, Yohimbine HCl, microcrystalline cellulose (Avicel PH102) and Methocel or Eudragit, at the various percentages noted in Table 1 below, were placed into a high-shear granulator and mixed for 15 minutes. Deionized (DI) water (approx. 40-100 g/min) was added slowly, and the wet granules were mixed for another 5-10 minutes.
Extruder and Spheronizer were then used to transform the wet granules into spheronized particles as follows. Three to four kilograms of wet granules were placed in Extruder apparatus. The feeder and impeller speeds were set at 45 rpm. The extruded "spaghetti" obtained from the extruder was charged into the spheronizer having a rotation setting of 800 rpm. After 5 - 10 minutes of spheronization, the bead-like pellets were discharged from the spheronizer. The spheronized pellets were then dried using Fluid-Bed dryer. The fluid bed dryer was warmed up until the product temperature reached 45°C for 5 minutes. The dryer inlet temperature that was set at between 45°C - 50°C, and the wet pellets were charged into the dryer. The drying continued until the LOD reached below 1.5%. The dried pellets were then discharged from the fluid-bed dryer and sized by passing through different screens.The dried pellets were then encapsulated into hard gelatin/HPMC capsules.

Table 2 Formulation
Ingredients/ Batch no. 1 2 3 4
% of ingredient
Yohimbine HCl 6 5 10 30
MCC 90 70 50 60
Methylcellulose 2 10 20 10
Eudragit 2 15 20 10
*note- Water used for wet granulation considered as evaporated during drying.
Methylcellulose and Eudragit can be replaced with any "retardant" excipient mentioned in description.

Dissolution profile-
Dissolution profile by using dissolution method as using standard dissolution apparatus and mediu as per person skilled in the art which is based on solubility of Yohimbine and requirement of formulation as per design.
Dissolution profile of above formulations mentioned in Table no 3.
USP apparatus I or II can be used with PRM 50 to 100
Table 3- Dissolution profile
Time in hours/ Batch no 1 2 3 4
1 5 3 10 30
2 15 10 20 40
4 30 20 40 60
6 50 40 60 80
8 70 60 80 95
10 80 70 95 99

Table 4- Sustained release Yohimbine HCl tablet

Ingredient/ Batch no. 1a 2a 3a 4a
Yohimbine 5 3 10 0.1
MCC 38.5 16.5 48.5 13
Starch 5 10 20 5
HPMC 50 70 20 80
Colliodal silicon dioxide 1 1 1 1
Magnesium stearate 0.5 0.5 0.5 0.9
HPMC mentioned as "Retardant" excipient in the formulation can be replaced with any retardant excipient mentioned in the description above.

It will be appreciated by those skilled in the art that various modifications and changes can be made without departing from the scope of the embodiments disclosed herein. Such modifications and changes are intended to fall within the scope of the embodiments disclosed herein, as defined by the appended claims.

,CLAIMS:I/We Claims-

1. A pharmaceutical formulation comprising a controlled-release Yohimbine or Alpha-Yohimbine.
2. The pharmaceutical formulation of Claim 1 wherein said controlled-release Yohimbine comprises a sustained release Yohimbine or Alpha-Yohimbine.
3. The pharmaceutical formulation of Claim 2 further comprising a retardant excipient configured to modify a dissolution profile of said sustained-release Yohimbine.
4. The pharmaceutical formulation of Claim 3, wherein said retardant excipient comprises at least one selected from hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose (HPC), methylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, microcrystalline cellulose, corn starch, polyethylene oxide, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl acetate phthalate, polyethylene glycol, zein, poly-DL-lactide-co-glycolide, dicalcium phosphate, calcium sulfate, and mixtures thereof.
5. The pharmaceutical formulation of Claim 3 or Claim 4, wherein the dissolution profile comprises a dissolution rate that is slower than a dissolution rate of a comparable immediate-release Yohimbine formulation under comparable conditions.
6. The pharmaceutical formulation of any one of Claims 3 to 5, wherein said dissolution profile comprises at least one dissolution characteristic selected from:
(a) less than about 70% of Yohimbine in the sustained-release Yohimbine is dissolved within a first hour in a standard dissolution test,
(b) less than about 40% of the Yohimbine in the sustained-release Yohimbine is dissolved within a first hour in a standard dissolution test,
(c) less than about 30% of the Yohimbine in the sustained-release Yohimbine is dissolved within a first hour in a standard dissolution test,
(d) less than about 75% of the Yohimbine in the sustained-release Yohimbine is dissolved within a second hour in a standard dissolution test,
(e) less than about 55% of the Yohimbine in the sustained-release Yohimbine is dissolved within a second hour in a standard dissolution test, and
(f) less than about 35% of the Yohimbine in the sustained-release Yohimbine is dissolved within a second hour in a standard dissolution test.
7. The pharmaceutical formulation of any one of Claims 3 to 6, wherein said pharmaceutical formulation comprises at least about 5% by weight of said retardant excipient.
8. The pharmaceutical formulation of any one of Claims 3 to 6, wherein said pharmaceutical formulation comprises at least about 10% by weight of said retardant excipient.
9. The pharmaceutical formulation of any one of Claims 3 to 6, wherein said retardant excipient is configured to provide, upon administration to a patient, an average free serum Yohimbine Cmax value that is less than an average free serum Yohimbine Cmax value of a comparable immediate-release Yohimbine under comparable conditions.
10. The pharmaceutical formulation of any one of Claims 3 to 6, wherein upon administration to a patient, an average free serum Yohimbine Cmaxvalue is at least about 5% less than an average free serum Yohimbine Cmax value of a comparable immediate- release Yohimbine under comparable conditions.
11. The pharmaceutical formulation of Claim 2, comprising sustained-release Yohimbine beads that are configured to control the dissolution profile of said sustained- release Yohimbine.
12. The pharmaceutical formulation of Claim 11, wherein said sustained- release Yohimbine beads comprise at least one of a filler and an excipient.
13. The pharmaceutical formulation of Claim 12, wherein said excipient comprises at least one selected from a cellulose ether, methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), corn starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), Tartaric acid, MCC, Sugar, Sucrose and cross-linked PVP.
14. The pharmaceutical formulation of Claim 12 or Claim 13, wherein said filler comprises at least one selected from acetyltriethyl citrate (ATEC), acetyltri-n-butyl citrate (ATBC), aspartame, lactose, alginates, calcium carbonate, carbopol, carrageenan, cellulose, cellulose acetate phthalate, croscarmellose sodium, crospovidone, dextrose, dibutyl sebacate, ethylcellulose, fructose, gellan gum, glyceryl behenate, guar gum, lactose, lauryl lactate, low-substituted hydroxypryopl cellulose (L-HPC), magnesium steafate, maltodextfin, maltose, mannitol, methylcellulose, microcrystalline cellulose, methacrylate, sodium carboxymethylcellulose, polyvinyl acetate phthalate (PVAP), povidone, shellac, sodium starch glycolate, sorbitol, starch, sucrose, triacetin, triethylcitrate, vegetable based fatty acid, xanthan gum, and xylitol.
15. The pharmaceutical formulation of any one of Claims 11 to 14, wherein said dissolution profile comprises at least one dissolution characteristic selected from:
(a) less than about 65% of the Yohimbine in the sustained-release Yohimbine beads is dissolved within the first hour in a standard dissolution test, and
(b) less than about 50% of the Yohimbine in the sustained-release Yohimbine beads is dissolved within the first hour in a standard dissolution test.
16. The pharmaceutical formulation of any one of Claims 1 to 15, configured in a dosage form
selected from twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, and once weekly.
17. A method of treatment comprising administering the pharmaceutical formulation of any one of Claims 1 to 16 to a patient in need thereof.

18. A method of treatment comprising administering a pharmaceutical formulation of any one of Claims 1 to 17 to a patient in need thereof, wherein the patient experiences a reduced risk of an adverse event associated with administering a comparable dosage of an immediate-release Yohimbine.
19. A method of making the pharmaceutical formulation of any one of Claims 1 to 16, comprising intermixing the Yohimbine with an effective amount of an excipient to form a mixture, and configuring the mixture into a unit dosage form.
20. The Pharmaceutical or Diatery formulation of claim 1 to 19, contains Yohimbine or any of the salt, ester, isomer, enantioner, polymorph, cocrystal or Premix of Yohimbine like Alpha-Yohimbine.