WO1996028244A1

WO1996028244A1 - Composition for stabilizing a suspension and pharmaceutical uses of said composition and of said suspension

Info

Publication number: WO1996028244A1
Application number: PCT/BE1996/000028
Authority: WO
Inventors: Jean-Paul Remon
Original assignee: Universiteit Gent
Priority date: 1995-03-14
Filing date: 1996-03-14
Publication date: 1996-09-19
Also published as: EP0814899A1; BE1009380A3; AU4933996A

Abstract

The composition which is suitable for stabilizing a suspension, preferably a pharmaceutical suspension or for the preparation of pharmaceutical matrix, comprises Xanthan gum and an N-octenylsuccinate starch.

Description

Composition for stabilizing a suspension and pharmaceutical uses of said composition and of said suspension

The present invention relates to a composition for stabilizing a suspension or an emulsion of liquid or solid particles, preferably pharmaceutical suspension, food suspension, phyto-pharmaceutical suspension, .... The invention relates also to the preparation of a hydrophilic matrix with a controlled release.

The stabilization of a suspension of solid particles is of major importance * for avoiding solid particles to form a deposit which can no more or with difficulty be suspended, and * for avoiding a too rapid coalescence and creaming of oil droplets to form large oil drops.

Xanthan gum is known as a thickening agent for aqueous liquid medium and is an agent used for the preparation of hydrophilic matrix.

N-octenylsuccinate starch is known as agent for increasing the solubility (International Journal of Pharmaceutics - 1993 - Elsevier Science Publishers B.V.- pages 23-27 - Remon et al) and as thickener agent for aqueous medium.

Researches made by the inventor have shown that N- octenylsuccinate starch was not efficient for stabilising suspensions of solid particles.

It has now been found that, when using together

Xanthan gum and a N-octenylsuccinate starch, an exceptional stabilization of suspension and emulsion could be achieved, whereby the solid particles of the suspension or the droplets of the emulsion were well dispersed in the suspension or in the emulsion or whereby solid particles or droplets could easely be dispersed.

When using Xanthan gum and a N-octenylsuccinate starch in the prepartion of a drug containing matrix, it has been observed that the matrix had a perfect texture and that the release rate of the drug could be controlled, for example a substantially constant release rate after administration.

A first subject matter of the invention is a composition containing Xanthan gum and a N- octenylsuccinate starch. Such a composition, for example in the form of dry powders, can be added to a suspension containing solid particles, for example an aqueous suspension possibly containg a solvent, an organic solvent, so as to stabilize the particles in said suspension. The composition of the invention is thus a composition for stabilizing a suspension of solid particles or an emulsion of liquid droplets, preferably pharmaceutical suspension, food suspension, phyto- pharmaceutical suspension, .... Advantageously, the weigth ratio Xanthan gum / N- octenylsuccinate starch in the composition is between 1/20 and 20/1, preferably between 1/15 and 15/1.

According to a first embodiment, the weigth ratio Xanthan gum / N-octenylsuccinate starch is higher than 1/5, advantageously higher than 1/4, but preferably lower than 1/1.

By using such weight ratio, the suspension of drug solid particles is stable and has a slow release of drug. A matrix made from such a composition has also a slow release rate. According to another embodiment, the weigth ratio Xanthan gum / N-octenylsuccinate starch is lower than 1/5, preferably lower than 1/8, for example 1/10. By using such weight ratio, the suspension of drug solid particles is stable and has a high release of drug. Matrix made from such a composition, which will be decomposed after administration (i.e. making a kind of suspension in the stomach) , has a high release rate.

The composition of the invention has preferably the form of a mixture of dry particles. However, said composition may have other forms, such as the form of a liquid (for example, an aqueous medium containing Xanthan gum and N-octenylsuccinate starch) , a pasta, ...

According to a preferred embodiment, the composition as described above is mixed with solid drug, said composition being mixed with a pharmaceutical drug containing solid particles before oral administration of the drug containing particles and/or during the oral administration of the drug containing particles and/or after the administration of the drug containing particles, so as to control the release of the drug administered.

The invention relates also to a suspension of solid particles, said suspension containing a composition as described above for increasing the stability of the suspension. Advantageously, the weight ratio solid particles to be suspended / composition according to the invention is between 15/1 and 1/15, preferably between 10/1 and 1/3, most preferably between 1/1 and 1/2.5. A further subject matter of the invention is a pharmaceutical drug form (pills, pellets, compressed tablets, ... ) containing :

* solid drug particles or solid particles containing a mixture of said drug and a solvent for said drug, and

* a composition as described above.

Preferably, the solid drug particles or solid particles containing a mixture of said drug and a solvent for said drug are dispersed into a matrix, the composition of which is a composition of the invention.

For example, the weight ratio solid particles / composition Xanthan gum + N-octenylsuccinate starch is between 15/1 and 1/15, preferably between 10/1 and 1/3, most preferably between 1/1 and 1/2.5.

According to a specific embodiment, the solid particles are microcrystalline particles containing the drug suspended in a solvent .

For example, the weight ratio Xanthan gum / N- octenylsuccinate starch of the pharmaceutical form is lower than 1/5, preferably lower than 1/8, for example 1/10 or lower than 1/10, whereby a higher release rate of the drug can be achieved at least 1 hour after administration, said higher release rate being substantially constant from a total release of 20% of the drug up to a total release of the drug of 90%.

According to another example, the weight ratio Xanthan gum / N-octenylsuccinate starch of the pharmaceutical form is higher than 1/5, advantageously higher than 1/4, but preferably lower than 1/1, whereby a slow release rate of the drug can be achieved at least 1 hour after administration, said slow release rate being substantially constant at least from a total release of 20% of the drug up to a total release of the drug of 90%. The pharmaceutical drug form is preferably a compressed mixture of drug containing particles, particles of Xanthan gum and particles of N- octenylsuccinate starch. In the pharmaceutical drug form of the invention, the weight ratio drug containing particles / composition as described above is between 10/1 and 1/2.

Preferably, the weight ratio drug containing particles / Xanthan gum is greater than 3/1, while the weight ratio drug containing particles / N- octenylsuccinate starch is lower than 3/1, most preferably between 1.5/1 and 1/4.

The invention relates further to drug containing solid particles covered with a layer having a composition as disclosed above. Preferably, the solid particles (advantageously microcrystalline particles) contain the drug and a solvent of said drug.

A still further subject matter of the invention is the use of a composition as disclosed above for increasing the efficiency of a pharmaceutical drug.

Details and characteristics of the invention will appear from the following description, in which reference is made to the attached drawings.

In said drawings,

Fig 1 shows the release of drug containing pharmaceutical form, and - Fig 2 to 5 show the stability of suspensions

Examples of pharmaceutical forms

Tablets containing Ibuprofen as drug have been prepared as follows : Ibuprofen (Ibu.) in the form of dry particles has been mixed with dry particles of Xanthan gum (Gum) and dry particules of N-octenylsuccinate starch (Sta.) . The so obtained mixture has then be mixed with magnesium stearate (Mag. ) .

The particles mixture has then been compressed (pressure of about 130 MPa) into tablets having a diameter of 9 mm.

The following table gives the parts by weight of the different ingredients which have been used for the preparation of the tablets.

Tablets 1 2 3 4

Ibu 100 100 100 100

(parts)

Gum 20 20 20 20

(parts)

Sta 80 200 20

(parts)

Mag 4 4 4 4

(parts) ratio Gu /Sta 1/4 1/10 1/1 1/1

The release of these tablets has been studied in an aqueous medium having a temperature of 37°C and containing a phosphate buffer ( pH : 7.2 ) . The release of these tablets in function of the time is shown in Fig

1.

As it can be seen from said figure, the release of tablet 1 was lower than the release of tablets 2 and 3. A 80% release was obtained for tablet 1 after 24 hours, while said 80 % release was obtained after 8 hours for tablet 2, and after 10 hours for tablet 3.

The release rate was substantially constant for the tablets 2, said release rate being about 13%/hour. For tablets with a high release rate it is important to avoid or to reduce the initial high release rate. For tablet 2, said high initial rate occurs about 1 hour after the beginning of the release, and being about 19% release instead of an expected value of about 13%. For tablet 3, such an initial high release occurs also about 1 hour after the beginning of the release, and being of about 26% release, instead of an expected value of about IGΪ. It means that when no N-octenylsuccinate starch is used, the initial release after 1 hour is more than 2.5 times higher than the expected release rate, while when using N-octenylsuccinate starch, the initial release rate is less than about 50% higher than the expected release.

As it can be seen from said figure, by modifying the weight ratio Xanthan gum/N-octenylsuccinate starch from 1/4 to 1/10 (i.e. by increasing the amount of N- octenylsuccinate starch used) , it is possible to control the release rate from about 4%/hour (slow release) up to about 13%/hour (high release) .

The release rate of tablet 4 was still lower than the release rate of tablet 2.

Example of suspensions

Suspensions of particles of paracetamol in 100 ml water have been prepared. The composition of the prepared suspensions is given below : Suspension SI S2 S3 S4

Water(ml) 100 100 100 100

Paracetamol

⁽g⁾

Sta (g) * 0.2

Gum (g) 0.5 0.5 0.5 0.5

* -. N-octenylsuccinate starch ** : Xanthan gum

The suspensions have been analyzed just after preparation ( ) ; 2 months after preparation ( ) ; 1 year after preparation without stirring or shaking and at a temperature of 20°C ( ) , and 1 year after preparation with stirring and/or shaking and with a temperature varying between 10 and 50°C ( ) .

The results of the analysis are shown in Fig 2 to 5, said Fig giving the percentage of particles with a diameter higher than 35, 70 and 105 μm.

It appears from these results that an agglomeration (formation of larger particles) of particles of the suspension containing no N- octenylsuccinate starch occurs after the preparation of the suspension. The number of particles with a higher diameter increased after the preparation of the suspension. As it can be seen from Fig 2, the increase of particles with a diameter larger than 105 μm is about 30% ( i.e. a relative increase of the numbers of particles with a diameter larger than 105 μm is about 100% - about 30 % 2 months after the preparation and about 60 % 1 year after the preparation ) . With respect to the increase of particles with a diameter larger than 70 μm, the number of particles was about 50 % 2 months after preparation, while said number was about 80 % after preparation. The relative increase of the number of particles with a diameter larger than 70 μm was (80- 50/50) 60%.

By using N-octenylsuccinate starch, it was possible to reduce the increase of the number of particles with a diameter larger than 75 μm and 105 μm to less than 10- 15 % (- increase between the number of particles 1 year after preparation and just after preparation) , i.e. a relative increase of less than (62-50/50) about 25% for the number of particles with a diameter larger than 70 μm.

Fig 3 and 4 show also that the number of particles with a diameter larger than 105 μm remains substantially constant and that said number (1 year after preparation) is substantially the same for the suspension without shaking and with shaking.

Said Fig 3 to 5 show that when using together

Xanthan gum and a N-octenylsuccinate starch, the particles of the suspension had a better stability, stability which was not dependent from the temperature and of the shaking or not. The simultaneous use of Xanthan gum and a N-octenylsuccinate starch acts as means for reducing the formation of larger particles and reduces the recrystallisation of larger particles.

Such pharmaceutical suspension containing

Xanthan gum and a N-octenylsuccinate starch has the advantage that 1 year after preparation, said suspension will have the same or substantially the same property or efficiency. Indeed, as t.-.a formation of larger particles is reduced or avoided (said particles forming a deposit on the bottom which can no more be suspended) , the drug content of the suspension remains substantially constant or the same just after preparation and one year after preparation. Furthermore, as the mean diameter of the particles just after preparation and the mean diameter of the particles one year after preparation will be substantially equal (there is no or substantially no formation of large particles) the efficiency of the particles suspended which depends of the size of the particles will remain substantially constant during at least one year.

Other suspensions containing drug particles have been prepared. In said other suspensions, the drug was ibuprofen, sulfonamide, antibiotics, ... The stability of said suspensions has also been observed.

The simultaneous use of Xanthan gum and a N- octenylsuccinate starch seems also to increase the efficiency of a drug, pharmaceutical active agent in a patient. This better efficiency seems to be due to a better repartition or dispersion of the pharmaceutical solid drug in the stomach of the patient, in the mouth of the patient, in the gastro intestinal track, .... The composition containing Xanthan gum and a N- octenylsuccinate starch can be mixed with pharmaceutical drug containing solid particles before oral administration of the drug containing particles and/or during the oral administration of the drug containing particles and/or after the administration of the drug containing particles, so as to control the release of the drug.

The suspensions 2 to 4 have been dried, whereby drug particles covered with a layer comprising Xanthan gum and a N-octenylsuccinate starch have been prepared. Said dried solid particles were suitable for the preparation of suspensions, for example aqueous suspension, said suspension being for example prepared just before oral administration.

A further suspension has been prepared. The suspension was obtained by mixing ( under stirring and at a temperature of 45°C) nifedipine (5g) , Polyethylene- glycol derivative (PEG-7, Henkel, Cetiol HE, a solvent for nifedipine) (60g) ; water (300g) and microcrystalline cellulose (50g) . To said mixture, 2g N-octenylsuccinate starch and 0.5g Xanthan gum was added. The suspension was a suspension of solid particles (microcrystalline particles) containing drug (nifedipine) and a solvent for said drug (PEG-7) , i.e. drug dissolved in the solvent .

Said suspension has been dried at a temperature of about 50°C, so as to obtain solid particles containing drug (nifedipine) and a solvent for said drug (PEG-7) , i.e. drug dissolved in the solvent, said particles being covered with an outer layer comprising Xanthan gum and a N-octenylsuccinate starch.

Claims

What I claim is :

1. A composition for stabilizing a suspension or a emulsion of liquid or solid particles, said composition containing Xanthan gum and a N- octenylsuccinate starch.

2. The composition of claim 1, in which the weigth ratio Xanthan gum / N-octenylsuccinate starch is between 1/20 and 20/1.

3. The composition of claim 1, in which the weigth ratio Xanthan gum / N-octenylsuccinate starch is higher than 1/5.

4. The composition of claim 1, in which the weigth ratio Xanthan gum / N-octenylsuccinate starch is higher than 1/4.

5. The composition of claim 4, in which the weigth ratio Xanthan gum / N-octenylsuccinate starch is lower than 1/1.

6. The composition of claim 1, in which the weigth ratio Xanthan gum / N-octenylsuccinate starch is lower than 1/5.

7. The composition of claim 1, said composition having the form of a mixture of dry particles.

8. The composition of claim 1, said composition having the form of a liquid mixture, preferably the form of a liquid aqueous mixture.

9. The composition of any of the claims 1 to 8 mixed with pharmaceutical drug containing solid particles, said composition being mixed with pharmaceutical drug containing solid particles before oral administration of the drug containing particles and/or during the oral administration of the drug containing particles and/or after the administration of the drug containing particles, so as to control the release of the drug.

10. A suspension of solid particles containing a composition according to any of the claims 1 to 8 for increasing the stability of the suspension.

11. The suspension of claim 10, in which the weight ratio solid particles / composition according to any of the claims 1 to 8 is between 15/1 and 1/15.

12. The suspension of claim 10, in which the weight ratio solid particles / composition according to anyone of the claims 1 to 8 is between 10/1 and 1/2.

13. A pharmaceutical drug form containing :

* a composition according to any of the claims 1 to 8.

14. The pharmaceutical drug form of claim 13, in which the solid drug particles or solid particles containing a mixture of said drug and a solvent for said drug are dispersed into a matrix, the composition of which is a composition according to any of the claims 1 to 8.

15. The pharmaceutical drug form of claim 13, in which the weight ratio solid particles / composition according to any of the claims 1 to 8 is between 15/1 and 1/15.

16. The pharmaceutical drug form of claim 13, in which the weight ratio solid particles / composition according to any of the claims 1 to 8 is between 10/1 and 1/2.

17. The pharmaceutical drug form of claim 13, in which the solid particles are microcrystalline particles containing the drug dissolved in a solvent.

18. The pharmaceutical drug form of claim 13, in which the weight ratio Xanthan gum / N-octenylsuccinate starch is lower than 1/5, whereby a high release rate of the drug can be achieved at least 1 hour after administration, said high release rate being substantially constant from a total release of 20% of the drug up to a total release of the drug of 90%.

19. The pharmaceutical drug form of claim 13, in which the weight ratio Xanthan gum / N-octenylsuccinate starch is higher than 1/5, whereby a slow release rate of the drug can be achieved at least 1 hour after administration, said slow release rate being substantially constant at least from a total release of 20% of the drug up to a total release of the drug of 90%.

20. The pharmaceutical drug form of claim 13, in which the matrix is a compressed mixture of drug containing particles, particles of Xanthan gum and particles of N-octenylsuccinate starch.

21. The pharmaceutical drug form of claim 13, in which the weight ratio drug containing particles / composition according to any of the claims 1 to 8 is between 10/1 and 1/2.

22. The pharmaceutical drug form of claim 13, in which the weight ratio drug containing particles / Xanthan gum is greater than 3/1.

23. The pharmaceutical drug form of claim 13, in which the weight ratio drug containing particles / N- octenylsuccinate starch is lower than 3/1.

24. The pharmaceutical drug form of claim 13, in which the weight ratio drug containing particles / N- octenylsuccinate starch is between 1.5/1 and 1/4.

25- Drug containing solid particles covered with a layer having a composition in accordance to any of the claims 1 to 8.

26. Drug containing solid particles of claim 25, in which the solid particles contain the drug and a solvent of said drug.

27. Drug containing solid particles of claim 25, in which the solid particles are microcrystalline particles containing the drug and a solvent of said drug.

28. Use of a composition of any of the claims 1 to 8 for increasing the efficiency of a pharmaceutical drug.