Method for pressing in preparing medicinal formulation of phenytoin sodium

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for pressing in preparing a medicinal formulation of phenytoin sodium, method for pressing in rollers and preparing a pharmaceutical composition involves stages of addition of phenytoin sodium into a mixer receiver and addition of at least one excipient into indicated mixer. Mixture is stirred and transferred into roller thickener wherein pressure is applied on the mixture of phenytoin sodium and excipient. The prepared compact-(briquette) is ground and prepared granulate is mixed repeatedly that is suitable from further processing to a medicinal formulation. Excipients involve magnesium stearate, sugar, lactose monohydrate and talc, or talc is added directly before the second mixing the granulate.

EFFECT: improved pressing method.

15 cl, 10 tbl, 2 dwg, 4 ex

 

The technical FIELD

The present invention relates to a method for producing dosage forms of phenytoin sodium. In particular, the present invention relates to a method for oral insertion of capsules phenytoin sodium with prolonged action.

PRIOR art

In the development of pharmaceutical technologies dosage form with prolonged action can be defined as a drug that releases the drug in vivo, at a much slower speed than is the case for conventional (neprolongirovannymi steps) of the dosage form with an equivalent dose. Purpose of use of the product with prolonged action is to obtain a satisfactory reaction to the drug, while reducing, at the same time, frequency of administration and the preservation of bioequivalence with respect to existing formulations of phenytoin sodium. An example of a medicinal product which is widely used in the form with prolonged action is chlorpheniramine. In the traditional form of the drug may be administered in the form of a 4-mg dose every 4 hours or in the form of prolonged action in the form of a single dose of 12 mg every 12 hours.

Compositions with prolonged action for serial or posted on BP is like the release of drugs known in this field. Typically, such compositions contain particles medicines is usually injected in divided doses 2 or 3 times a day, mixed with or covered with a substance that is resistant to degradation or disintegration in the stomach and/or intestines during the selected time period. The release of drug can occur by drainage, erosion, decay, diffusion or similar actions, depending on the application of the foregoing substances. In some cases, the release of hydrophilic substances from the composition can be slowed down by applying a hydrophobic substance.

It is known that various pharmaceutical products of the same active ingredient may have different bioavailability of the active component in relation to the mammal. Bioavailability or biological availability can be defined as the proportion (percentage) of drug released from the entered dosage form, which is available for the manifestation of biological actions in the body. Different formulations of the same drug may vary in bioavailability in the clinically relevant range, and this deviation can occur even between batches of the same product due to subtle changes in the terms of the production process.

Many of the medicinal product, which is usually administered in the form of tablets or capsules, have low solubility in biological fluids. For many drugs with low solubility are obvious evidence that the rate of dissolution partially or completely affect the speed of absorption. In addition, the bioavailability can be affected by several factors, such as the number and types used adjuvants, granulation, compression forces (at reception of tablets), the surface area available for dissolution and environmental factors, such as movement (content) in the gastrointestinal tract and the presence of food. Due to the above, numerous factors specific composition plays an important role in the preparation of solid dosage forms with prolonged action. Solid dosage forms with prolonged action can be of great interest for the treatment of diseases, such as epilepsy.

Epilepsy is an ancient disease that affects approximately 1% of the world's population. Despite the progress made in the treatment of antiepileptic drugs, still there are many patients who continue to suffer from uncontrolled seizures and toxicity of drug therapy. Examples of the main antiepileptic drug which means, currently used are: sodium salt of divalproate acid, tosucceed, sodium phenytoin, carbamazepine and valproic acid.

Pharmacological activity in General and protivoepilepticheskie activity in particular is better correlated with the concentration of the drug in the blood (or other biophase)than with the input dose. This phenomenon is due, in part, the variability in absorption and distribution of drugs between different people and within organisms, particularly when the drug is administered orally. Optimization of drug therapy strives to achieve and maintain a therapeutic and safe concentrations of the drug in the plasma of the patient.

Phenytoin, 5,5-diphenyl-2,4-imidazolidinedione is a known pharmaceutical agent with anticonvulsant and antiepileptic activity. Due to the lack of solubility of phenytoin in water for injectable solutions of drugs in solid dosage forms using phenytoin sodium, which is much better soluble in water.

Phenytoin sodium has the following formula:

Although phenytoin is preferred anti-epileptic medication for many types of epileptic joke is s, required therapeutic drug monitoring because of the difficulty of maintaining an effective therapeutic level of the drug in plasma is between 10 μg/ml and 20 μg/ml in Addition to problems associated with a narrow therapeutic plasma levels of phenytoin demonstrates significant variations in bioavailability after oral administration to patients because of its lack of solubility in water.

Even in the case of new approaches to the delivery of phenytoin (i.e. dosage forms Dilantin® Kapseals®proposed by Parke-Davis, which represent 100-mg capsules phenytoin sodium with prolonged action), patients still need to take medication several times a day in order to maintain effective therapeutic plasma levels without side effects. If Kapseals® action in vivo product is characterized by slow and stretched over time, the rate of absorption with peak concentrations in the blood observed after 4-12 hours.

Despite the fact that have been tried numerous methods and methods with the aim of obtaining reliable dosage forms of phenytoin, comparable with Dilantin® Kapseals®and there was none that would be entirely satisfactory. Karakasa et al., Biol. Pharm. Bull., 1994; 17(3):432-436 in an article entitled "Sustained Release of henytoin Following the Oral Administration of Phenytoin Sodium/Ethylcellulose Microcapsules in Human Subjects and Rabbits," described Issledovanie picture (profile) release of phenytoin in the form of sodium salt in combination with ethylcellulose. Microcapsules with phenytoin sodium was obtained by mixing 80 wt.% phenytoin sodium 10 wt.% a solution of ethyl cellulose in ethyl acetate. The suspension was stirred and to it was added dropwise n-pentane until then, there were observed no phase separation, and the obtained microcapsules. Microcapsules were collected on filter paper, dried and preserved. Karakasa, etc. pay attention to the fact that after oral administration of phenytoin sodium specified salt could easily be transformed into acidic fluids of the stomach in free phenytoin. Since the free phenytoin practically insoluble in water, its absorption in the gastrointestinal tract could be incomplete. On the other hand, when passing through the stomach, the amount of water penetrating into ethylcellulose microcapsules could be minimal. Thus, most of phenytoin sodium microcapsules could not become free phenytoin.

In a review article Boxenbaum in Drug Development &Industrial Pharmacy, 1982; 8(v):1-25, entitled "Physiological and Phamacokinetic Factors Affecting Performance of Sustained Release Dosage Forms", in fact, argues that the compositions of the slow release for drugs such as phenytoin, are not necessary. Boxenbaum notes that the regimen of medicines once daily compared with regimen 3 times daily give similar plasma curves This is the result of slow absorption, and the low solubility of the drug.

Aspirational goal - phenytoin with slow release, delayed (delayed) release, extended (prolonged) - release or long (continuous) release. Oral dosage forms with controlled release of drugs with a long half-life existence, such as phenytoin, for a composition with prolonged action was ignored, as they give a small change in the concentration in the blood after administration of multiple doses. The existence of the above-mentioned products may, however, be justified on the basis of their ability to minimize toxicity and the manifestation of adverse reactions, and that they provide greater convenience for patients and, thus, are highly preferred in patients.

In the publication Bourgeois entitled "Important Pharmacokinetic Properties of Antiepileptic Drugs" in Epilepsia, 1995;36 (Supp.5), discusses the important pharmacokinetic properties of antiepileptic drugs. The author argues that the profile of the extent of drug absorption is described by the constant of absorption (Kabs). The high value of the constant absorption leads to early and high peaks of serum concentrations. A high value (Kabs) also leads to a more strong the m level fluctuations of the drug compared with the more stable concentrations, resulting from lower values (abs). The lower the value of the constant absorption can often be obtained when formulating otherwise rapidly absorbed drugs in the drug slow release. However, the use of drugs with intersolubility coating as part of the method of producing the dosage form does not change the value (Kabs) medicines, they only slow down the absorption. Intersolubility coating is designed to prevent the absorption in the acidic environment of the stomach. Consider, for example, a patient who received a single dose of valproate, covered intersolubility shell. Within the first few hours after taking a dose of serum measurement will not detect the drug in the blood. Only when the tablet reaches the alkaline environment of the duodenum, serum concentration starts to increase rapidly, eventually reaching a profile similar to the profile of the drug valproate without coating. Therefore, intersolubility floor only shifts the profile (curve) concentration-time right.

From a review of the prior art it is obvious that there is still a need to develop methods that could easily and reliably to provide the dosage form with the prolon the new action for drug solubilities, dependent on pH, such as phenytoin sodium, a form that provides the initial therapeutic levels of drugs and slows the release of another part of the medicinal product, to avoid excessive concentration over a period of time from about 1 to 5 hours. The methods according to the present invention are useful for dosage forms of phenytoin sodium, which is, essentially, a suitable dissolution profile.

The INVENTION

The present invention implements the unmet needs described above by providing a method of a light receiving part, which has a given ratio to the desired dose. In those cases, when phenytoin sodium is an active pharmaceutical component, the composition demonstrates bioequivalence with respect to dosage forms Dilantin® Kapseals®. Specifically, the present invention includes a method of pressing rollers for solid granules, after which encapsulate give a predictable dissolution profile. In particular, the present invention includes a method of pressing rollers to get solid granules, after which encapsulate give a mostly constant dissolution profiles among different lots messageserver composition, includes source effervescent phenytoin sodium. Furthermore, the method provides a reliable and stable product of phenytoin sodium. Therefore, regular application of this method provides a reliable way to get dosage forms of phenytoin sodium, and ensures appropriate product performance.

In General, the present invention provides a method of obtaining a pharmaceutical product. The method includes the stage of addition of phenytoin sodium in a container or tank of the mixer and adding at least one excipient in the tank. The mixture is then stirred to obtain a mixture. The resulting mixture is transferred to a roller compactor and pressed between at least two rollers, receiving briquette with excipients. The pressure applied to the mixture, improves physical adhesion between phenytoin and excipients. Then the briquettes are crushed to form granules. Then the resulting granules are molded into a desired dosage form, such as capsules.

In one embodiment of the invention the method includes the stage of addition of phenytoin sodium in the tank mixer; add excipient in the tank; mixing of phenytoin sodium and filler with the first mixture; pressing the first mixture between at least two rolls force sufficient to cause the crushing part of phenytoin sodium and the formation of the briquette, where the first mixture is subjected to processing rollers with a force of between 1 and 20 kN (kN, kN), rolls rotate at the same speed between 1 and 20 rpm, and where the outer surfaces (edges) of the above-mentioned rolls are fixed in their position of closest approach at a distance of between 0.5 mm and 5 mm from each other; grinding briquette to form granules; mixing the granulate to obtain a second mixture.

In another embodiment of the invention the force of rollers affixed to the first mixture, 2.5 kN, here, rolls rotate with a speed of 10 rpm, and the working gap between the rollers is 3 mm.

In another embodiment, the excipients include magnesium stearate, sugar and lactose monohydrate, and the method includes a step of mixing the talc with a granulate of phenytoin sodium. Alternatively, the talc may be included as one of the excipients, originally mixed with phenytoin sodium in the tank.

Further, patients will benefit from such a composition, since many drugs such as phenytoin sodium, have a narrow therapeutic window, which usually require multiple (three or more) daily techniques.

It must be borne in mind that both the foregoing description and the following detailed description are illustrative, but are not restrictive of the volume is and inventions.

The invention is best understood when considering the following detailed description in conjunction with the accompanying following drawings, in which:

Figure 1 is a graphic showing the dissolution of the mixture obtained by the method according to the present invention at various compression forces, using the same values of the gap between the rollers and the rotational speed of the rolls.

Figure 2 is a graphic showing the dissolution profiles of two formulations of phenytoin sodium obtained by the method according to the present invention, compared with the dissolution profile of the dosage form Dilantin® Kapseals®.

DETAILED description of the INVENTION

The present invention includes a method of roll-pressing, which is applied to the mixture of the active pharmaceutical component and one or more excipients, to produce pellets with corresponding characteristics. In particular, the present invention provides a method of producing granules of active pharmaceutical component - phenytoin sodium.

The method according to the present invention includes the use of the device for pressing the rolls, with the possibility to adjust the speed of the rolls, the magnitude of the efforts of the rolls and the working gap between the rollers. The press system is of the dry materials in rolls of the type Gerteis Polygran, having a 100 mm corrugated (thumb) rolls produced Gerteis (Germany), is the preferred device for pressing the rolls as programmable logic control system of the above-mentioned roller seal is relatively simple in operation.

Roller compactor operates through a uniform application of pressure to the mixed powder mixture, passing the mixture between two rotating in the opposite direction the rollers. Pressure, is passed into a mixture of rollers which presses the powder into briquette, such as a sheet or tape, which is usually crushed, receiving granules.

The method according to the present invention relates to the discovery, according to which some therapeutic agents, such as phenytoin sodium, can be formulated and processed to obtain the dosage form providing a prolonged concentration of active pharmaceutical agents in the blood plasma. Specialists in this field it is obvious that the effective number released during a specified period of time, providing the desired concentration in the blood plasma.

It was found that the controlled application of pressure to a mixture of the active pharmaceutical component and at least one excipient when pressing in rolls yields a product that, besides the fact that his is relatively easy to obtain, demonstrates the prolonged release properties in a reproducible way. In addition, in the case of phenytoin sodium, the product is bioequivalent to the commercial Dilantin® Kapseals®. In particular, we can assume that during pressing in the rolls of the mixture obtained in accordance with the present invention, the components are in a state of close contact, forced mixing and adhesion. Particles undergo rearrangement, and, presumably, the crushing of the particles generates numerous parts of the surface, the points of contact and areas of the binding between the active pharmaceutical ingredient and excipients. Increasing contact between the active pharmaceutical ingredient and excipients directly affects the characteristics of dissolution of the active pharmaceutical component. In other words, we can assume that one or more excipients to form a coating, dissolution inhibiting medicines around the active pharmaceutical component after exposure to pressure reported roller compactor. This approach enables the development of a reproducible method of producing dosage forms of phenytoin sodium.

In particular, the present invention includes a method of pressing rollers for solid Gras is str, after encapsulating give essentially the same dissolution profile for lots of different mixtures dosed composition comprising the same initial bulk phenytoin sodium.

It is implied that the term "basically the same" dissolution profile means that the difference in dissolution, expressed in percent, between any two parties of the composition of the bulk phenytoin sodium is not more than 15% when measured under the same conditions (e.g. temperature and time) well-known methods in this field, including the methods illustrated here. More preferably, this difference ranges from 10% to 15%, even more preferably from 5 to 10%, and even more preferably from 2 to 5%; most preferably from 0% to 2%.

To achieve the objective of the present invention, the active pharmaceutical component is placed in the tank of the mixer, such as mixer with double casing type Patterson-Kelley®. Preferably, the active pharmaceutical ingredient phenytoin sodium. Unless otherwise noted, the percentage of the components are expressed in wt.%. Typically, the active pharmaceutical component is present in amount from about 25% to 75% of the total weight of the final dosage forms. Preferably, in tank add 35% to 50%.

Then excipients, such as on omnitele and lubricants, placed in the tank of the mixer with an active pharmaceutical ingredient, although the order of addition is not critical and may be reversed. To the mixture may be added a variety of lubricants are well known in this field, such as stearic acid and magnesium stearate. The lubricating substance can be added in amounts from about 1% to about 10% by weight of the total mixture, preferably from 2% to 5%.

In addition, the present invention may contain at least one filler as excipient. Suitable fillers are known in this area and usually include microcrystalline cellulose, sorbitol, mannitol, a sugar glaze, compressible sugar, glucose, monohydrate lactose and talc. Preferably, the icing, glucose monohydrate, compressible sugar, or a combination of add in the amount of approximately from 25% to 75% by weight of the total mixture. Talc may be added in amounts from about 0.5% to 5% by weight of the total mixture. Despite the fact that talc can be added to the tank mixer with other fillers, alternative talc may be added to the mixture immediately before additional stage of mixing, as described below. Preferably, one or more components, before they are added to the tank, first it is purified, for example, missing components h is through a sieve. In cases when the mixer used in the methods of the invention is a faucet with double case, the above mixer optionally includes stimulating the rod. By "stimulating the rod" means the rod containing the blades, which rotate in the direction opposite to the direction of rotation of the double casing. The use of such rods to improve the mixing of the powder layer, it is well known in this field.

After adding all components to the tank, the mixer is brought into action and the mixture is stirred tank mixer. One such mixer of the above-described type, which can be used in the present invention is a mixer Patterson-Kelley®. The powder mixture is placed in a mixer and stirred for from about 10 to 60 minutes at a rotational speed of from about 5 to about 30/min

Then the mixture is transferred to a roller compactor in a known manner. Then set the rotation speed of the rolls, the gap between the rollers and the compression force and the mixture is fed through the roller seal in a known manner. In particular, in the method according to the present invention is pressed mixture of phenytoin sodium and excipients in the briquettes making the best effort to get the brick. You can find predpochtite the optimum compression force and other conditions in order to ensure sufficient adhesion between the components, which will allow you to implement a suitable dissolution profile. The person skilled in the art can establish the above factors empirically. As for the roller seal Gerteis, the optimal value of effort is usually between 1 and 20 kN. For this type of seal is the optimal value of effort is preferably between 2 and 6 kN, more preferably 2.5 kN.

To maintain a constant outow of matter from the roll of sealer rollers rotate at a speed ranging from 1 to 20 rpm, Preferably the rolls rotate at speeds from 5 to 15 rpm in Addition, the outer surfaces of the rolls is fixed at a distance of between 0.5 mm and 5 mm from each other, and the outer surfaces of the rolls are preferably fixed in their position of closest approach at a distance of between 2 mm and 4 mm from each other. Although variations in the rotational speed of the rolls and the gap between the rollers have an impact on the dissolution profile of phenytoin sodium, the force of the rolls is the most important parameter, as described above, and detailed in Example 3.

After contact with the oppositely rotating rollers roller sealer compressive force supplied to the mixture rolls, turns powdery mixture in the tape or pressed sheet. Then received the output briquette is fed to the mill, usually a vibrating mill with sieve. Preferably, the sieve has a hole diameter between 0.2 mm and 2 mm, most preferably about 1.0 mm After passing through the mill and sieve cake turns into a granulate.

After grinding the granules are transferred into the mixer and stirred in a similar manner as described above, receiving a second mixture. However, if talc is not added to the operation of pressing together with other fillers, it can, if necessary, be added before the above-mentioned second stage of mixing. After carried out the mixture a second time, the resulting mixture can be encapsulated in a known manner, as, for example, by using the machine to encapsulate Hofliger & Karg. Granules can be filled into the body of the dosage form capsules by trebovaniya or dispensing, and then the capsule can be sealed with caps-cap.

As shown in figure 1, the effort plays an important role in the dissolution of phenytoin sodium. In particular, it was found that the greater the force applied to the mixture, fed into the roller compactor, the lower the degree of dissolution at constant speeds of the rolls and the gap between the rollers. Accordingly, by adjusting the pressure applied to the mixture of the active component and excipient, havemay in the roll seal, it is possible to reproducibly control the dissolution profile of phenytoin sodium dosage form. In addition, as shown in figure 2, dosage form obtained by the method according to the present invention has a release profile similar to the profile of release dosage forms Dilantin® Kapseals®.

EXAMPLE 1

Get a mixture of phenytoin sodium and excipients in amounts shown in Table 1. The mixture is stirred for 10 minutes in the mixer Patterson-Kelly®.

Table 1

The composition of the mixture
Components% of the total mass
Sodium phenytoin, USP43,5%
Magnesium stearate, NF3,9%
Compressible sugar, NF24,9%
Talc, USP2,7%
The lactose monohydrate, NF25,0%

EXAMPLE 2

To determine the range in which stress plays a role in the dissolution of the granules obtained by the method according to the present invention, the parameters of the method - the gap between the rolls and the roll rotational speed, constant support, as detailed below. Table 2 presents data of dissolution of a portion of the mixture described in Example 1, pressed under various efforts Valk the century The percentage of dissolved drug determine, using standard protocols known in the field. In particular, use the test for dissolution USP for each of the formulations of phenytoin sodium. In particular, this test includes the location of each capsule in 900 ml of water, which is supported at 37°C±0,5°C and stirred at 50 rpm Samples taken at 30, 60 and 120 minutes and examined for the number contained dissolved phenytoin sodium.

Table 2

The influence of compression force on dissolution
The parameters are:

roller gap = 2 mm, the rotation speed of rolls = 3 rpm,

the force of the rolls (kN)
Dissolution (%)

(sd)

n=12
30 min60 min120 min
5 kN32 (1,5)55 (3,4)74 (3,7)
8 kN29 (1,4)46 (2,1)62 (3,6)
11 kN31 (2,2)46 (3,1)61 (4,4)
14 kN29 (2,9)43 (4,1)57 (5,4)
17 kN32 (2,4)47 (3,0)62 (3,4)
(sd) - mean quadratic rejected the e

The data presented in Table 2 indicate that as the strength of the roll increases, up to 14 kN, the number of phenytoin sodium, which dissolves to 120 minutes, is reduced.

EXAMPLE 3

To determine the range over which the compressing force, as such, affects the dissolution, all of the parameters are kept constant, except for the efforts of the rolls, as detailed in Table 2 above. However, Table 3 summarizes the data of dissolution of different samples of the mixture described in Example 1 at different values of the magnitude of the efforts of the rolls, the size of the working gap between the rollers (the distance between the outer surfaces of the rolls in their position of closest approach) and different speeds of rotation of the rolls. Analogously to Example 2, the percentage of dissolved drug determine, using standard protocols known in the field.

Table 3

The influence of parameters of the method
The parameters of the methodDissolution (%)

(sd)

n=12
Party Experience noRoller gap (mm)Rolls rotating speed (rpm)The force of the rolls (kN)30 min 60 min120 min
12,56,07,029 (2,0)49 (3,2)66 (4,4)
22,03,03,033 (2,9)62 (5,7)81 (4,7)
32,56,011,027 (2,3)43 (2,6)59 (3,8)
43,03,011,027 (1,9)44 (2,3)60 (3,8)
52,06,011,028 (1,2)44 (2,9)59 (4,4)
62,06,011,029 (2,1)45 (2,8)60 (3,8)
72,56,07,028 (1,9)46 (5,1)65 (6,4)
83,09,011,027 (2,1)43 (2,7)60 (4,0)

From Table 3 we can see that the force of the rolls, undoubtedly, plays a predominant role in determining the dissolution profile of the product, medicinal product, obtained in the present invention. For example, comparison of dissolution data from experiments 1, 3 and 7 indicate that HC is the increase in the efforts of the rolls reduces the degree of dissolution (%). On the other hand, the statistical analysis found that the gap between the rollers and the speed of rotation of the rolls do not have the same degree of influence on the degree of dissolution.

EXAMPLE 4

Were further tested the method using various preparations of granular matter-of phenytoin sodium. Unless otherwise noted, all methods and parameters were the same as described above. Used the same components and mass relationships, which are presented in Table 1, with an optional replacement of the compression of sugar on the icing. The data are summarized below in Tables 4-10 and show that for a given bulk drug substance phenytoin sodium is achieved in essentially the same dissolution profiles.

In the case of the present invention were evaluated three bulk drugs (I, II and III) of phenytoin sodium. For bulk drug substances I phenytoin sodium 80% of the particles typically have a size of between 3-126 microns; median (50Ipercentile) of a particle size of about 15 to 23 microns (estimated Coulter counting). The dissolution profiles for bulk drug substances I phenytoin sodium depicted in Tables 2, 4, 5, 6, 8, and 9.

For bulk drug substances II phenytoin sodium 45-70% of the particles typically have a size of greater than or equal to 179 microns and 5-30% of the particles had a size large is, than or equal to 44 microns (evaluated by sieve analysis). The dissolution profiles for bulk drug substances I phenytoin sodium are given in Table 10.

Bulk drug substance III phenytoin sodium, probably mostly has a very small particle size; installed median less than 15 microns.

tr>
Table 4

The dissolution profiles of the capsules phenytoin sodium containing bulk drug substance I of phenytoin sodium
Lot noMethod: Force (kN)Speed (rpm), Clearance (mm)Used lots of phenytoin Na% each used lot% Dissolved (sd)
30 min60 min120 min
A3,2 kN 7,0 rpm, 2.6 mm191,8315271
28,2(0,8)(1,7)(2,6)
B3,4 kN, 6,5 rpm, 2.4 mm2100254565
(1,4)(2,2)(1,8)
C3,0 kN 7,5 rpm, 2.8 mm370,8284969
429,2(1,4)(2,2)(3,3)
D3, 2 kN 7,0 rpm, 2.6 mm548,5294970
651,5(2,8)(3,5)(3,2)
E3,3 kN, 6,8 rpm, 2.5 mm548,5274667
651,5(2,2)(3,3)(3,2)
F3,1 kN, 7,3 rpm, 2.7 mm748,5305070
851,5(1,5)(2,4)(3,2)
The range of parameters method: Force rolls from 3.0 to 3.4 kN

The speed of rotation of the rolls of 6.5 to 7.5 rpm

The gap between the rollers 2.4 to 2.8 mm

Table 5

The party made full scale (900 kg) to demonstrate the reproducibility of the method
Press the W in rolls

Lot no
% Dissolved
30 min60 min120 min
G1305273
H1305273
I1315475
J1325575
K1345978
L1346281
M1356182
N1386382
O1355878
P1315374
Q1315475
(Party A, table 4)315271
(Part D, table 4)294970
Average325676
The mean square error (SE)0,721,21,1
Median315475
Fashion (Mode) 315275
Standard deviation (SD)2,64,44,0
Parameters: Power = 3,2 kN, speed = 7,0 rpm,

Gap = 2.6 mm

Table 6

Parameter optimization method that uses a roller compactor Gerteis
The seal rolls Party No.Description of the parameters of the method% dissolved drug (SD)
30 min60 min120 min
Q1Power=2,0 kN

Constant speed and gap
36 (2,6)61 (2,9)82 (2,3)
Q2Power=2.5 kN *

Constant speed and gap
33 (2,0)58 (3,3)80 (2,5)
Q3Power=3,0 kN *

Constant speed and gap
33 (1,5)56 (2,8)76 (2,1)
Q4Gap=2.5 mm

Constant speed and power
34 (1,5)56 (2,5)76 (2,3)
Q5Power=2.5 kN *

Constant speed and the Azor
33 (2,0)57 (3,4)77 (2,8)
Q6Gap=3.5 mm

Constant speed and power
33 (1,2)56 (3,0)76 (3,1)
Constant speed = 10 rpm; Constant force = 2.5 kN; and a constant gap = 3,0 mm

* Duplicate parameters

Table 7

These dissolution for various parties, obtained with the use of bulk drugs III phenytoin sodium
Pressing in bulks Party No.Options% dissolved drug (SD)
30 min60 min120 min
R1Power=6,0 kN, Gap=2.0 mm, speed=8,0 rpm38 (3,2)71 (2,7)86 (1,2)
S1Power=10 kN, Gap=2.0 mm, speed=8,0 rpm31 (2,9)58 (2,9)78 (1,8)
R2Power=6,0 kN, Gap=2.0 mm, speed=12,0 rpm40 (4,3)74 (5,5)88 (2,7)
S2Power=10,0 kN, Gap=2.0 mm, speed=12,0 rpm34 (2,) 65 (2,5)86 (2,1)
R3Power=6,0 kN, Gap=4.0 mm, speed=8,0 rpm45 (3,9)71 (3,9)87 (3,1)
S3Power=10,0 kN, Gap=4.0 mm, speed=8,0 rpm32 (4,0)61 (4,5)80 (3,1)
U1Power=6,0 kN, Gap=4.0 mm, speed=12,0 rpm39 (4,0)78 (2,3)90 (0,6)
U2Power=10,0 kN, Gap=4.0 mm, speed=12,0 rpm35 (2,1)69 (3,9)87 (2,1)
S4Power=8,0 kN * Gap=3.0 mm, speed=10,0 rpm34 (2,9)65 (3,1)85 (2,6)
R4Power=8,0 kN * Gap=3.0 mm, speed=10,0 rpm40 (2,6)68 (2,3)85 (2,1)
U3Power=8,0 kN * Gap=3.0 mm, speed=10,0 rpm37 (1,7)71 (1,4)87 (1,4)
* Duplicate a Central point

Table 8

These dissolution for various parties, obtained using the bulk drug substance I of phenytoin sodium
Pressing in bulks Party No.Options% dissolved drug (SD)
30 min60 min120 min
V1Power=2,0 kN, Gap=2.5 mm, speed=8,0 rpm34 (1,3)58 (1,0)76 (0,8)
V2Power=3,0 kN, Gap=2.5 mm, speed=8,0 rpm32 (1,9)56 (2,1)75 (1,4)
V3Power=2,0 kN, Gap=2.5 mm, speed=12,0 rpm32 (1,0)56 (1,6)75 (2,0)
W1Power=3,0 kN, Gap=2.5 mm, speed=12,0 rpm34 (2,3)56 (2,2)75 (2,4)
W2Power=2,0 kN, Gap=3.5 mm, speed=8,0 rpm34 (3,2)57 (4,2)74 (2,8)
W3Power=3,0 kN, Gap=3.5 mm, speed=8,0 rpm32 (2,1)56 (2,3)75 (1,7)
X1Power=2,0 kN, Gap=3.5 mm, speed=12,0 rpm33 (2,5)58 (1,9)76 (1,4)
X2Power=3,0 kN, Gap=3.5 mm, speed=12,0 rpm33 (0,8)56 (1,2)75 (2,3)
X3Power=2.5 kN, *

Gap=3.0 mm,

Speed=10,0 rpm
34 (3,1)56 (3,8)74 (2,8)
W4Power=2.5 kN, *

Gap=3.0 mm,

Speed=10,0 rpm
32 (0,8)53 (1,0)72 (1,6)
V4Power=2.5 kN, *

Gap=3.0 mm,

Speed=10,0 rpm
32 (1,7)56 (1,1)75 (0,8)
* Duplicate a Central point

Table 9

Parameter optimization method in a pilot scale (40 kg)
Phenytoin sodium

Lot number-

Seal in rolls

Lot no
% dissolved drug (SD)
30 min60 min120 min
I-a33 (1,9)57 (2,7)77 (2,1)
I-b34 (1,1)59 (1,9)78 (2,3)
II-c35 (3,1)60 (2,6)79 (2,3)
III-d34 (1,5)59 (2,3)78 (1,9)
IV-e32 (1,2)57 (2,4)77 (2,6)
Power=2.5 kN; Gap=3.0 mm, speed=10,0 rpm

Table 10

Parameter optimization method using bulk drug substances II phenytoin sodium
Pressing in bulks Party No.Description of the parameters of the method% dissolved drug (SD)
30 min60 min120 min
X-1C=10 kN, W=3 mm, Cur.=12 rpm27 (1,3)44 (1,2)61 (1,5)
X-2C=8 kN, H=4 mm, Cur.=4 rpm27 (1,2)46 (1,8)65 (1,0)
X-3C=12 kN, W=2 mm, Cur.=8 rpm25 (1,5)41 (2,1)58 (2,3)
X-4C=6 kN, H=2.5 mm, Cur.=10 rpm28 (1,8)46 (2,6)65 (2,3)
Y-1C=2.5 kN, W=3 mm, Cur.=12 rpm26 (1,3)43 (2,1)62 (2,4)

The data presented above indicate that different batches of formulations of phenytoin sodium, obtained by the methods according to the invention and from the same bulk phenytoin sodium, demonstrate, mainly Odie is W hat is the dissolution profile.

Although the present invention is illustrated and described herein with reference to some specific options for its implementation and examples, however, understood that the present invention is not limited to the described individual parts. Rather, it should be considered that the claims includes various modifications within the scope and range of equivalents of the claims, without going beyond being present invention.

1. A method of obtaining a pharmaceutical composition that includes phenytoin sodium, by dry granulation, including

a) the addition of phenytoin sodium in the tank of the mixer;

b) adding at least one excipient in the specified reservoir;

c) mixing the specified excipient and specified phenytoin sodium with the formation of the mixture;

d) pressing this mixture into pellets;

e) grinding the specified briquette with the formation of the granules.

2. The method according to claim 1, where the specified phenytoin sodium added to the specified tank in the amount of 15-45% of the total mass of the specified granules.

3. The method according to claim 1, where at least one specified excipient selected from the group consisting of at least one compound from among stearic acid, magnesium stearate, microcrystalline cellulose, with the bits mannitol, a sugar glaze, compressible sugar, glucose, monohydrate lactose and talc.

4. The method according to claim 3, where the specified stearate, sugar, monohydrate lactose and talc added in the amount of approximately 25-75% of the total mass of the specified granules.

5. The method according to claim 3, where the specified stearate is added in the amount of 0.5-5% of the total mass of the specified granules.

6. The method according to claim 3, where talc is added in the amount of 0.5-5% of the total mass of the specified granules.

7. The method according to claim 1, where the specified phenytoin sodium is added in the amount of 35-55% of the total mass of the specified granules.

8. The method according to claim 1, where the stage of pressing includes pressing the specified phenytoin sodium and at least one of the specified excipient with roller seal having at least two rolls.

9. The method of claim 8, where the stage of pressing includes pressing the specified phenytoin sodium and at least one excipient with effort 1-20 kN between these rollers, where these rolls rotate with a speed 1-20 rpm and where the external surfaces of the rolls above is fixed at a distance of 1-5 mm from each other.

10. The method according to claim 9, where the stage of pressing includes pressing the specified phenytoin sodium and at least one of the specified excipient with force 2-5 kN between these rollers, where these rolls rotate with what korostil 5-12 rpm and the outer surfaces of the above rolls is fixed at a distance of 2-4 mm from each other.

11. The method according to claim 10, further comprising a stage of forming the above-mentioned mixture in dosage form by encapsulating parts of this mixture.

12. A method of obtaining a pharmaceutical composition that includes phenytoin sodium, by dry granulation, including

a) the addition of phenytoin sodium in the tank of the mixer;

b) adding excipient specified in the tank, and the specified excipient selected from the group consisting of at least one compound from among stearic acid, magnesium stearate, microcrystalline cellulose, sorbitol, mannitol, sugar, icing, compression of sugar, glucose and lactose monohydrate;

c) mixing the specified phenytoin sodium and specified excipient with the formation of the first mixture;

d) pressing the specified first mixture into pellets;

e) grinding the specified briquette with the formation of the granulate;

f) adding talc to the specified granulate;

g) mixing the specified granules with the formation of the second mixture.

13. The method according to item 12, where the specified phenytoin sodium added to the specified tank in the amount of 25-75% of the total mass of this mixture.

14. A method of obtaining a pharmaceutical composition that includes phenytoin sodium, by dry granulation, including

a) adding Antoine sodium in the tank of the mixer;

b) adding excipient specified in the tank, and the specified excipient selected from the group consisting of at least one compound from among stearic acid, magnesium stearate, microcrystalline cellulose, sorbitol, mannitol, a sugar glaze, compressible sugar, glucose, monohydrate lactose and talc;

c) mixing the specified phenytoin sodium and specified excipient with the formation of the first mixture;

d) pressing the specified first mixture between at least two rollers with a force sufficient to cause fragmentation of the part specified phenytoin sodium and the formation of the briquette, and these rolls is applied to the said first mixture with a force of 1 kN to 20 kN, these rolls rotate with a speed of 1 to 20 rpm, and the outer surfaces of these rolls are fixed in their position of closest approach at a distance of 1-5 mm from each other;

e) grinding the specified briquette with the formation of the granulate;

f) mixing the specified granules with the formation of the second mixture.

15. The method according to 14, where the pressing of phenytoin sodium and at least one excipient carried out with a force of about 2.5 kN between the rollers and rotating with a speed of 10 rpm and the outer surfaces of these rolls is fixed at a distance of 3 mm from each other.



 

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