Liquisolid systems and methods of preparing same

• US 5,800,834 A
• Filed: 06/10/1996
• Issued: 09/01/1998
• Est. Priority Date: 06/10/1996
• Status: Expired due to Term

• Current Assignee: Hygrosol Pharmaceutical Corp.
• Original Assignee: Hygrosol Pharmaceutical Corp.
• Inventors: Spireas, Spiridon, Bolton, Sanford M.
• Primary Examiner(s): Krass, Frederick
• Application Number:
  US08/658,514
• Time in Patent Office: 813 Days
• Field of Search: 264/5, 264/6, 264/7, 264/40.4, 424/451, 424/452, 424/456, 424/457, 424/458, 424/459, 424/461, 424/462, 424/464, 424/465, 424/468, 424/489, 424/490, 424/493, 424/494, 424/497, 424/501
• US Class Current: 424/451
• CPC Class Codes: A61K 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00

Abstract

Liquisolid systems are acceptably flowing and compressible powdered forms of liquid medications. According to the concept of liquisolid systems, liquid lipophilic drugs, or water-insoluble solid drugs dissolved in suitable non-volatile solvents, may be converted into free-flowing and readily compressible powders by a simple admixture with selected powder excipients referred to as the carrier and coating materials. Various grades of microcrystalline or amorphous cellulose may be used as carriers, whereas very fine particle size silica powders may be used as coating materials. Based on the theory that the carrier and coating materials can retain only certain amounts of liquid and at the same time maintain acceptable flow and compression properties, a new formulation-mathematical model is provided to calculate the optimum quantities of carrier and coating materials required to yield acceptably flowing and compressible liquid/powder admixtures.

Claims

1. A method of producing a free-flowing and readily compressible liquid/powder admixture of a liquid medication, which involves converting the liquid medication into a liquisolid system, comprising the steps of:

(a) selecting a weight (W) of the liquid medication to be included in a single liquisolid compact;

(b) selecting a carrier material and a coating material to be included in the liquisolid system;

(c) determining the characteristic minimum carrier;

coating ratio, R_min, and flowable liquid-retention potentials of the carrier (Φ

) and coating (φ

) materials using a liquisolid flowability test;

(d) determining the characteristic compressible liquid-retention potentials of the carrier (Ψ

) and coating (ψ

) materials using a liquisolid compressibility test;

(e) selecting a carrier;

coating ratio, R, where R>

R_min, of the carrier and coating materials to be included in the liquisolid system, where R=Q/q, Q=the weight of carrier material, and q=the weight of coating material;

(f) calculating the optimum liquid load factor (L_o) of the system according to the equations;

space="preserve" listing-type="equation">L.sub.o =.sup.Φ

L.sub.f when .sup.Φ

L.sub.f <

.sup.Ψ

L.sub.f

or

space="preserve" listing-type="equation">L.sub.o =.sup.Ψ

L.sub.f when .sup.Φ

L.sub.f >

.sup.Ψ

L.sub.f

where;

space="preserve" listing-type="equation">.sup.Φ

L.sub.f =Φ

+φ

(1/R)

and

space="preserve" listing-type="equation">.sup.Ψ

L.sub.f =Ψ

+ψ

(1/R)

(g) calculating the optimum quantities of the carrier (Q_o) and coating (q_o) materials according to the equations;

space="preserve" listing-type="equation">Q.sub.o =W/L.sub.o

space="preserve" listing-type="equation">q.sub.o =Q.sub.o /R

(h) admixing the liquid medication with the calculated quantity of carrier material (Q_o); and

(i) blending the resulting wet mixture with the calculated amount of coating material (q_o) to produce a nonadherent, free-flowing and compressible liquid/powder admixture.

2. The method of claim 1, further comprising the step of mixing the liquid/powder admixture with an amount of lubricant effective for tabletting or encapsulating the liquid/powder admixture.

3. The method of claim 2, further comprising the step of adding to the liquid/powder admixture an amount of disintegrant effective to produce liquisolid compacts possessing immediate drug release properties.

4. The method of claim 2, further comprising the step of adding to the liquid/powder admixture an amount of binder effective to produce liquisolid compacts possessing sustained drug release properties.

5. The method of claim 1, wherein the liquid medication is a drug solution, a drug suspension or a liquid drug.

6. The method of claim 5, wherein the drug solution and drug suspension each comprises a solid water-insoluble drug in a solvent and the liquid drug is a liquid lipophilic medication.

7. The method of claim 3, wherein the liquisolid compacts are tablets or capsules.

8. The method of claim 4, wherein the liquisolid compacts are tablets or capsules.

9. The method of claim 1, wherein the carrier material comprises a porous material possessing sufficient absorption properties to permit absorption of the liquid medication into the carrier material.

10. The method of claim 9, wherein the carrier material is microcrystalline cellulose or amorphous cellulose.

11. The method of claim 1, wherein the coating material comprises a material having a fine particle size in the range of about 10 nm to 5,000 nm and possessing sufficient adsorptive properties to permit adsorption of the coating material onto the wet mixture, thereby converting the wet mixture into the, nonadherent, flowable and compressible liquid/powder admixture.

12. The method of claim 11, wherein the coating material is an amorphous silicon dioxide.

13. The method of claim 1, wherein the liquisolid flowability test of step (c) comprises:

(a) preparing several powder systems each containing a carrier material and a coating material and selecting for each system a carrier;

coating ratio, R₁ . . . x, where ₁ . . . x corresponds to the powder systems prepared,

R₁ . . . x =Q₁ . . . x /q₁ . . . x,

R₁ . . . x =Q₁ . . . x =the weight of the carrier material, and

q₁ . . . x =the weight of the coating material;

(b) preparing several uniform liquid/powder admixtures of different liquid/solid weight compositions (C_w) by combining one of the powder systems prepared in step (a) with increasing amounts of the solvent included in the liquid medication of claim 6;

(c) assessing the flow rate and consistency of the admixtures thus obtained using a recording powder flowmeter and determining from this assessment the flowable liquid load factor (.sup.Φ

L_f) of the powder system which complies with a pre-selected limit of acceptable flowability, where .sup.Φ

L_f =W/Q, W=the weight of the liquid and Q=the weight of the carrier material;

(d) repeating steps (b) and (c) for the remaining powder systems of step (a) to determine the flowable liquid load factors of these systems; and

(e) plotting the flowable liquid load factors (.sup.Φ

L_f) thus obtained against the corresponding reciprocal carrier;

coating ratios (1/R) of the powder systems, thereby obtaining a linear plot having a Y-intercept equal to the flowable liquid-retention potential of the carrier material (Φ

) and a slope equal to the flowable liquid-retention potential of the coating material (φ

).

14. The method of claim 1, wherein the liquisolid compressibility test of step (d) comprises:

(a) preparing several powder systems each containing a carrier material and a coating material and selecting for each system a carrier;

coating ratio, R₁ . . . x, where ₁ . . . x corresponds to the powder systems prepared,

R₁ . . . x =Q₁ . . . x /q₁ . . . x,

Q₁ . . . x =the weight of the carrier material, and

q₁ . . . x =the weight of the coating material;

(b) preparing several uniform liquid/powder admixtures of different liquid/solid weight compositions by combining one of the powder systems prepared in step (a) with increasing amounts of the solvent included in the liquid medication of claim 6;

(c) compressing each liquid/powder admixture thus obtained into tablets using plateau compressional force to achieve maximum tablet crushing strength;

(d) assessing the average tablet crushing strength, S_c, of the tablets produced and calculating their pactisity, Ω

, where Ω

=S_c /W_t and W_t =the average tablet weight in grams;

(e) determining the average liquid content of the crushed tablets and calculating the net liquid/solid weight composition (C_w) of the crushed liquid/powder admixture;

(f) determining the characteristic intrinsic pactisity, Ω

_o, and sponge index, σ

_i, of the powder system by plotting the data obtained as log Ω

versus C_w, where log Ω

=log Ω

_o -σ

_i.C_w ;

(g) determining the Ψ

_mix of the powder system, where Ψ

_mix =(log Ω

_o -log

     20)/σ

_i ;

(h) determining the compressible liquid-load factor (.sup.Ψ

L_f) of the powder system, where .sup.Ψ

L_f =Ψ

_mix (1+1/R);

(i) repeating steps (b) through (h) for the remaining powder systems of step (a) to determine their compressible liquid load factors; and

(j) plotting the compressible liquid load factors thus obtained against the corresponding reciprocal carrier;

coating ratios (1/R) of the powder systems, thereby obtaining a linear plot having a Y-intercept equal to the compressible liquid-retention potential of the carrier material (Ψ

) and a slope equal to the compressible liquid-retention potential of the coating material (ψ

).

15. A method of producing a free-flowing liquid/powder admixture of a liquid medication, which involves converting the liquid medication into a liquisolid microsystem, comprising the steps of:

(a) selecting a weight (W) of the liquid medication to be included in a single liquisolid microsystem;

(b) selecting a carrier material and a coating material to be included in the liquisolid microsystem;

(c) determining the characteristic minimum carrier;

coating ratio, R_min, and flowable liquid-retention potentials of the carrier (Φ

) and coating (φ

) materials using a liquisolid flowability test;

(d) selecting a coating;

carrier ratio, R, where R>

R_min, of the carrier and coating materials to be included in the liquisolid microsystem, where R=Q/q, Q=the weight of carrier material, and q=the weight of coating material;

(e) calculating the optimum liquid load factor (L_o) of the system according to the equations;

space="preserve" listing-type="equation">L.sub.o =.sup.Φ

L.sub.f when .sup.Φ

L.sub.f <

.sup.Ψ

L.sub.f

or

space="preserve" listing-type="equation">L.sub.o =.sup.Ψ

L.sub.f when .sup.Φ

L.sub.f >

.sup.Ψ

L.sub.f

where;

space="preserve" listing-type="equation">.sup.Φ

L.sub.f =Φ

+φ

(1/R)

and

space="preserve" listing-type="equation">.sup.Ψ

L.sub.f =Ψ

+ψ

(1/R)

(f) calculating the optimum quantities of the carrier (Q_o) and coating (q_o) materials according to the equations;

space="preserve" listing-type="equation">Q.sub.o =W/L.sub.o

space="preserve" listing-type="equation">q.sub.o =Q.sub.o /R

(g) admixing the liquid medication with the calculated quantity of carrier material (Q_o); and

(h) blending the resulting wet mixture with the calculated amount of coating material (q_o) to produce a nonadherent, free-flowing liquid/powder admixture.

16. The method of claim 15, further comprising the step of mixing the liquid/powder admixture with an amount of lubricant effective for encapsulating the liquid/powder admixture.

17. The method of claim 16, further comprising the step of adding to the liquid/powder admixture an amount of disintegrant effective to produce liquisolid microsystems possessing immediate drug release properties.

18. The method of claim 16, further comprising the step of adding to the liquid/powder admixture an amount of binder effective to produce liquisolid microsystems possessing sustained drug release properties.

19. The method of claim 15, wherein the liquid medication is a drug solution, a drug suspension or a liquid drug in combination with polyvinylpyrrolidone.

20. The method of claim 19, wherein the drug solution and drug suspension each comprises a solid water-insoluble drug in a solvent and the liquid drug is a liquid lipophilic medication.

21. The method of claim 15, wherein the carrier material comprises a porous material possessing sufficient absorption properties to permit absorption of the liquid medication into the carrier material.

22. The method of claim 21, wherein the carrier material is microcrystalline cellulose or amorphous cellulose.

23. The method of claim 15, wherein the coating material comprises a material having a fine particle size in the range of about 10 nm to 5,000 nm and possessing sufficient adsorptive properties to permit adsorption of the coating material onto the wet mixture, thereby converting the wet mixture into the, nonadherent, flowable and compressible liquid/powder admixture.

24. The method of claim 23, wherein the coating material is an amorphous silicon dioxide.

25. The method of claim 15, wherein the liquisolid flowability test of step (c) comprises:

(a) preparing several powder systems each containing a carrier material and a coating material and selecting for each system a carrier;

coating ratio, R₁ . . . x, where ₁ . . . x corresponds to the powder systems prepared,

R₁ . . . x =Q₁ . . . x /q₁ . . . x,

Q₁ . . . x =the weight of the carrier material, and

q₁ . . . x =the weight of the coating material;

(b) preparing several uniform liquid/powder admixtures of different liquid/solid weight compositions (C_w) by combining one of the powder systems prepared in step (a) with increasing amounts of the solvent included in the liquid medication of claim 34;

(c) assessing the flow rate and consistency of the admixtures thus obtained using a recording powder flowmeter and determining from this assessment the flowable liquid load factor (.sup.Φ

L_f) of the powder system which complies with a pre-selected limit of acceptable flowability, where .sup.Φ

L_f =W/Q, W=the weight of the liquid and Q=the weight of the carrier material;

(d) repeating steps (b) and (c) for the remaining powder systems of step (a) to determine the flowable liquid load factors of these systems; and

(e) plotting the flowable liquid load factors (.sup.Φ

L_f) thus obtained against the corresponding reciprocal carrier;

coating ratios (1/R) of the powder systems, thereby obtaining a linear plot having a Y-intercept equal to the flowable liquid-retention potential of the carrier material (Φ

) and a slope equal to the flowable liquid-retention potential of the coating material (φ

).