WO2005046651A1 - Liquid filled capsules of doxycycline - Google Patents

Abstract

The present invention relates to stable liquid filled capsule of Doxycycline and the process of preparation thereof.

Description

LIQUID FILLED CAPSULES OF DOXYCYCLINE

Field of the Invention

The present invention relates to stable liquid filled capsule of Doxycycline and the process of preparation thereof. Background of the Invention

Doxycycline is a broad spectrum antibiotic synthetically derived from oxytetracycline and is available as doxycycline nionohydrate; doxycycline hyclate; doxycycline hydrochloride hemiethanolate hemihydrate; and doxycycline calcium for oral administration. It is also available as doxycycline hyclate for intravenous use as well as coated pellets.

Doxycycline has a high degree of lipid solubility and low aqueous solubility i.e. it is hydrophobic in nature. Tablet containing doxycycline hydrochloride tends very easily to stick to the mucosa in the esophagus causing irritation and ulceration.

U.S. Patent No. 4,693,997 relates to a complex of careageenan and 10-70% by weight of said complex of doxycycline, calculated as doxycycline hydrochloride, which comprises reacting in solution carrgeenan or a salt thereof with doxycycline or and salt thereof to thereby provide said complex.

U.S. Patent No. 6,294,192 discloses a capsule for oral administration comprising a hydrophobic therapeutic agent and a carrier comprising atleast one hydrophilic surfactant selected from a group consisting of hydrophilic non-ionic surfactant, hydrophilic ionic surfactants and combination thereof and a solubilizer selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.

The above given references show that doxycycline is either administered as a complex or in combination with various carriers, thus resulting in a reduction of esophageal irritation and ulceration. Summary of the Invention

Hence in one aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a non-aqueous base as a carrier. In another aspect it provides a stable bioequivalent liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from polyglycohzed glycerides, Triacetin or Vegetable oils.

When two carriers with different HLB values are used in combination the dispersibility of the carrier can further be improved by addition of Soyalecithin.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from Polyglycohzed glycerides, such as Com oil PEG-6 Esters (marketed by Gattefosse as Labrafil® M 2125 CS and Labrafil® M 1944 CS).

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Triacetin as a carrier. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from vegetable oils such as Miglyol or Soyabean oil.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Com oil PEG-6 Esters and Triacetin as a carrier.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Com oil PEG-6 Esters and Miglylol as a carrier.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglylol as a carrier. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a carrier selected from Polyglycohzed glycerides such as Com oil PEG-6 Esters, wherein the ratio of doxycycline to Com oil PEG-6 Esters is in the range of 1 :0.5 to 1:5 and more particularly in the range of 1 : 1 to 1:2.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Triacetin as a carrier wherein the ratio of doxycycline to triacetin is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Miglyol as a carrier wherein the ratio of doxycycline to Miglyol is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2.

Li another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters, and Triacetin as carrier wherein their ratio is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1 :1 to 1 :2.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters, and Miglyol as carrier wherein their ratio is in the range of 1 :0.5 to 1:5 and most preferably in the range of 1 : 1 to 1 :2.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglyol as carrier wherein their ratio is in the range of 1 :0.5 to 1 :5 and most preferably in the range of 1:1 to 1:2.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Polyglycohzed glycerides such as Com oil PEG-6 Esters as a carrier for the treatment of bacterial infections. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and triacetin as a canier for the treatment of bacterial infections.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Miglylol as a carrier for the treatment of bacterial infections.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Corn oil PEG-6 Esters and triacetin as carrier for the treatment of bacterial infections.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Polyglycohzed glycerides such as Com oil PEG-6 Esters and Miglyol as carrier for the treatment of bacterial infections. In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a combination of Triacetin and Miglyol as carrier for the treatment of bacterial infections.

In another aspect it provides a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and a canier selected from Polyglycohzed glycerides, Triacetin or Vegetable oils, wherein the capsule is a soft gelatin capsule or a hard gelatin capsule.

In another aspect it provides a stable liquid filled capsule comprising doxycycline and a non-aqueous carrier selected from Polyglycohzed glyceride and/or Triacetin and/or Miglyol having dissolution of at least 70% in 60 min as measured using USP 24 Type 2 paddle type apparatus at 75 rpm, in a dissolution medium constituted by 0.1N HC1.

Detailed Description of the invention

In the present invention we have found that capsules containing an active amount of doxycycline in few particular carrier quickly displays the desired activity without oesophageal irritation and ulceration. The use of wax bases as carrier led to product that is not bioequivalent, and hydrophilic bases resulted into change in coloration when subjected to 40/75%RH for 5 days. It was found that doxycycline in combination with certain non- aqueous bases remains stable and results in a bioequivalent dosage form. The tenn "Liquid filled" refers to the ingredients, which are liquid when filled in the capsule. This liquid can later turn into semisolid or remain as a liquid when the capsule is sealed.

In one of the embodiments stable liquid filled softgelatin capsule comprising doxycycline is prepared by rotary die process. The fill liquid may be prepared by mixing Doxycycline and the carrier alone or in combination in the ratio of 1 : 1. This mixture is passed through a colloidal mill to form a homogeneous dispersion. The remaining quantity of carrier is added and mixed with the homogeneous dispersion.

The fill formulation is encapsulated into one-piece gelatin sheath or shell that includes a plasticizer to control the softness and flexibility of the sheath, water, and optionally, other additives, such as flavorants, colorants, opacifiers, etc. The softgel capsules are produced in a known manner with a rotary die process in which a molten mass of a gelatin sheath formulation is fed from a reservoir onto drums to form two spaced sheets or ribbons of gelatin in a semi-molten state. These ribbons are fed around rollers and brought together at a convergent angle into the nip of a pair of roller dies that include opposed die cavities. A fill formulation to be encapsulated is fed into the wedge-shaped joinder of the ribbons.

The gelatin ribbons are continuously conveyed between the dies, with portions of the fill formulation being trapped between the sheets inside the die cavities. The sheets are then pressed together, and severed around each die so that opposed edges of the sheets flow together to form a continuous gelatin sheath around the entrapped medicament. The part of the gelatin sheet that is severed from the segments forming the capsules is then collected for recycling, and the soft capsules are dried. The sheath plasticizer preferably is sorbitol, sorbitol special (a mixture of sorbitol and sorbitan), maltitol, glycerin or a mixture thereof

The sheath formulations may also contain other ingredients, such as taste modifiers, coloring agents, and moisture retaining agents. Various FD&C coloring agents may be used to impart the desired color to the capsule.

In another embodiment stable liquid filled hard gelatin capsule comprising doxycycline and a carrier is prepared by mixing doxycycline and the a part of carrier alone or in combination. This mixture is passed through a colloidal mill to form a homogeneous dispersion. The remaining quantity of carrier is added and mixed with the homogeneous dispersion. The resulting dispersion is then filled into hard gelatin capsules.

The invention is further illustrated by the following examples, which is for illustrative purpose only and should not be considered as limiting the scope of the invention in any way.

Table 1: EXAMPLE 1 - 3

PROCEDURE:

1. Doxycycline and Com oil PEG-6 Esters or Triacetin in the ratio of 1 : 1 alone or in combination are mixed.

2. The ingredients of step 1 are passed through a colloidal mill to fonn a homogenous dispersion.

3. The remaining quantity of Com oil PEG-6 Esters or Triacetin are mixed to the homogeneous dispersion of step 2.

4. The dispersion of step 3 is then incorporated in soft gelatin capsules of suitable size. Table 2: EXAMPLE 4 - 5

PROCEDURE:

1. Doxycycline, Soyalecithin and Triacetin or Miglyol in the ratio of 1 : 1 alone or in combination are mixed.

2. The ingredients of step 1 are passed through a colloidal mill to form a homogenous dispersion.

3. The remaining quantity of Triacetin or Miglyol are mixed to the homogeneous dispersion of step 2. 4. The dispersion of step 3 is then incorporated in hard gelatin capsules of suitable size.

In vitro dissolution study

In vitro release of doxycycline from capsules as per composition of Example 1-4 was studied in 900 ml, 0.1 N HCl, (pH-1.2), using USP apparatus - II, at 75 rpm. The results are listed in Table 3. Table 3: In vitro release of doxycycline from capsules

In Vivo Bioavailability Study

In vivo performance of doxycycline softgelatin capsules prepared as per the composition of Example 1 were evaluated with respect to the Monodox in 12 healthy male volunteers under fasting condition. The study protocol followed was randomized treatments, single dose crossover bioavailability study on Doxycycline 100 mg soft gelatin capsules under fasting condition with a wash out period of at least 10 days. Blood samples were collected at appropriate time intervals over a period of 96 hours and doxycycline content analyzed using a validated HPLC with UV detector method. Pharmacokinetic parameters C_max (Maximum plasma concentration), AUC_0-t (Area under the plasma concentration vs time curve from 0 hours to the time of last sample collected) and AUC_0-a (Area under the plasma concentration vs. time curve from 0 hours to infinity) were calculated from the data obtained. The results of the study are given in Table 4.

Table 4: Comparative pharmacokinetic data

The soft gelatin capsules demonstrated comparable extent of absorption when compared to the reference Monodox.

While there has been shown and described what are the prefened embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the fonnulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.

Claims

WE CLAIM:

1. A stable liquid filled capsule comprising doxycycline and a non-aqueous carrier selected from Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil having a dissolution of at least 70% in 60 min as measured using USP 24 Type 2 paddle type apparatus at 75 rpm, in a dissolution medium constituted by 0.1N HCl.

2. The stable liquid filled capsule according to Claim 1 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1:0.5 to 1:5.

3. The stable liquid filled capsule according to Claim 2 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1 : 1 to 1:2.

4. The stable liquid filled capsule according to Claim 1 wherein the carrier is selected from Polyglycohzed glyceride such as Com oil PEG-6 Esters.

5. The stable liquid filled capsule according to claim 4 wherein carrier is Com oil PEG- 6 Esters.

6. The stable liquid filled capsule according to Claim 1 wherein the carrier is Triacetin.

7. The stable liquid filled capsule according to Claim 1 wherein the carrier is selected from vegetable oils such as Miglyol or Soyabean oil.

8. The stable liquid filled capsule according to Claim 7 wherein the carrier is Miglyol.

9. The stable liquid filled capsule according to claim 1 wherein carrier is a combination of Com oil PEG-6 Esters and Triacetin.

10. The stable liquid filled capsule according to claim 1 wherein carrier is a combination of Com oil PEG-6 Esters and Miglyol.

11. The stable liquid filled capsule according to claim 1 wherein carrier is a combination of Triacetin and Miglyol.

12. The stable liquid filled capsule according to claim 1 wherein it is either a softgelatin or hard gelatin capsule.

13. A process for preparation of a stable liquid filled capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil as a carrier by mixing doxycycline and a part of carrier; then passing through a colloid mill to form a homogeneous mixture, to which the remaining quantity of carrier is added and finally filled into capsules.

14. The process according to claim 13 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1 : 0.5 to 1:5.

15. The process according to claim 14 wherein the ratio of doxycycline to the Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil is in the range of 1 : 1 to 1 :2.

16. The process according to claim 13 wherein carrier is selected from Polyglycohzed glycerides such as Corn oil PEG-6 Esters.

17. The process according to claim 13 wherein the carrier is Triacetin.

18. The process according to claim 13 wherein the carrier is selected from Vegetable oils such as Miglyol.

19. The process according to claim 13 wherein carrier is a combination of Com oil PEG- 6 Esters and Triacetin.

20. The process according to claim 13 wherein carrier is a combination of Com oil PEG- 6 Esters and Miglyol.

21. The process according to claim 13 wherein carrier is a combination of Triacetin and Miglyol.

22. A stable bioequivalent liquid filled softgelatin capsule comprising doxycycline or a pharmaceutically acceptable salt thereof and Polyglycohzed glyceride and/or Triacetin and/or Vegetable oil as a carrier as described and illustrated herein.