Structured orthoester and orthocarbonate drug delivery devices

• US 4,131,648 A
• Filed: 03/02/1978
• Issued: 12/26/1978
• Est. Priority Date: 01/28/1975
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Heller, Jorge, Choi, Nam S.
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US05/882,814
• Time in Patent Office: 299 Days
• Field of Search: 424/14, 424/16, 424/19-22, 424/32, 424/78, 128/260
• US Class Current: 424/484
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2853 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

The invention concerns orthoester and orthocarbonate polymers having a repeating mer comprising a hydrocarbon radical and a symmetrical dioxycarbon unit of the general formula: ##STR1## WHEREIN R₁ is a multivalent hydrocarbon radical, R₂ and R₃ are hydrocarbon radicals with at least one of R₂ or R₃ bonded to the dioxycarbon through an oxygen linkage, and which polymers are synthesized by reacting a polyol with an orthoester or orthocarbonate. The polymers are useful for making articles of manufacture, including devices and coatings for delivering beneficial agents.

Claims

1. A drug delivery device for the controlled administration of drug wherein the device comprises:

(a) a matrix shaped, sized and adapted for administering drug to an animal and formed of a hydrophobic, bioerodible, drug release rate controlling material, which material is a copolymer comprising mers I and II according to the following formula;

##STR61## wherein R₁ is a member selected from the group consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with a member selected from the group consisting of alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, an alkenyl of 2 to 7 carbons; and

wherein a is 0 to 1;

b is 2 to 6;

m is greater than 10;

n is greater than 10; and

at least one of R₁, a, and b in mer I is different than R₁, a, and b in mer II;

a drug present in the matrix; and

(c) wherein the device when in operation bioerodes and releases drug at a rate selected from (1) a zero order rate, (2) a continuous rate, and (3) a variable rate, which rate is produced by preselecting the copolymer, the drug, and the geometric shape forming the device to give the desired result.

2. A drug delivery device for the controlled administration of drug wherein the device comprises (a) a matrix shaped, sized and adapted for administering drug to an animal and formed of a hydrophobic, bioerodible, drug release rate controlling material, which material is comprising mers I, II, and III according to the following formula:

##STR62## wherein R₁ is a member selected from the group consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with a member selected from the group consisting of alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, an alkenyl of 2 to 7 carbons; and

wherein a is 0 to 1;

b is 2 to 6;

m is greater than 10;

n is greater than 10;

p is greater than 10; and

at least one of R₁, a, and b in mers I, II and III is different than R₁, a, and b in mers I, II and III;

(b) a drug present in the matrix; and

(c) wherein the device when in operation bioerodes and releases drug at a controlled rate selected from (1) a zero order rate, (2) a continuous rate, and (3) a variable rate, which different rate is achieved by preselected the terpolymer, the drug and the geometric shape forming the device.

3. A drug delivery device for the controlled and continuous administration of drug, wherein the device comprises:

(a) a matrix shaped, sized and adapted for placement in an animal environment for administering drug thereto;

(b) a multiplicity of microcapsules housed in the matrix with the microcapsules having a wall formed of a drug release rate controlling material;

(c) a drug selected from the group consisting of locally and systemically acting drugs in the microcapsules;

said matrix formed of a bioerodible drug release rate controlling pharmaceutically acceptable material, which material comprises a polymer of the formula;

##STR63## wherein R₁ is a member selected from the group of divalent, trivalent and tetravalent radicals consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;

R₂ and R₃ are selected from the group consisting of alkyl of 1 to 7 carbons;

alkenyl of 2 to 7 carbons;

alkoxy of 1 to 7 carbons;

alkenyloxy of 2 to 7 carbons;

alkylene of 2 to 6 carbons;

alkenylene of 3 to 6 carbons;

alkyleneoxy of 2 to 6 carbons;

alkenyleneoxy of 3 to 6 carbons;

aryloxy;

aralkyleneoxy of 8 to 12 carbons;

aralkenyleneoxy of 8 to 12 carbons;

oxa;

OR₁ O with R₁ as defined above;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and alkenyl of 2 to 7 carbons formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons;

an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons; and

wherein at least one of said R₂ and R₃ is a member selected from the group consisting of alkoxy, alkenyloxy and OR₁ O;

R₂ and R₃ when taken together are a member selected from the group of heterocyclic and fused polycyclic rings having at least one oxygen atom in the ring; and

wherein n is greater than 10;

(d) wherein, when the device is in operation, the matrix and the microcapsules bioerode at a controlled and continuous rate over a prolonged period of time, thereby administering a therapeutically effective amount of drug to the animal at a controlled and continuous rate over a prolonged period of time.

4. A drug delivery device for the controlled and continuous administration of drug, wherein the device comprises:

(a) a matrix shaped, sized and adapted for administering drug to an animal, said matrix comprising multilayers formed of different bioerodible drug release rate controlling pharmaceutically acceptable materials, selected from materials which comprise a polymer of the formula;

##STR64## wherein R₁ is a member selected from the group of divalent, trivalent and tetravalent radicals consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;

R₂ and R₃ are selected from the group consisting of alkyl of 1 to 7 carbons;

alkenyl of 2 to 7 carbons;

alkoxy of 1 to 7 carbons;

alkenyloxy of 2 to 7 carbons;

alkylene of 2 to 6 carbons;

alkenylene of 3 to 6 carbons;

alkyleneoxy of 2 to 6 carbons;

alkenyleneoxy of 3 to 6 carbons;

aryloxy;

aralkyleneoxy of 8 to 12 carbons;

aralkenyleneoxy of 8 to 12 carbons;

oxa;

OR₁ O with R₁ as defined above;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons;

an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons formed when R.sub. 2 and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons; and

wherein at least one of said R₂ and R₃ is a member selected from the group consisting of alkoxy, alkenyloxy and OR₁ O;

R₁ and R₃ when taken together are a member selected from the group of heterocyclic and fused polycyclic rings having at least one oxygen atom in the ring; and

wherein n is greater than 10;

(b) a drug selected from the group consisting of locally and systemically acting pharmaceutically acceptable drugs present in the layers; and

, (c) wherein, when the device is in operation, the layers bioerode at a controlled and continuous rate over a prolonged period of time, thereby administering a therapeutically effective amount of drug to the animal at a controlled and continuous rate over a prolonged period of time.

5. The drug delivery device for the controlled administration of drug according to claim 4, wherein the matrix is multilayered with at least two layers distant from each other with a layer formed of a different material positioned between the distant layers, with the distant and different layers formed of said bioerodible drug release rate controlling materials, which materials when the device is in operation bioerode into innocuous products.

6. A drug delivery device for the controlled and continuous administration of drug, wherein the device comprises:

(a) a matrix shaped, sized and adapted for administering drug to an animal;

(b) a plurality of discrete, closed cells in the matrix, said cells having a wall formed and defined by the matrix;

said matrix formed of a bioerodible drug release rate controlling pharmaceutically acceptable material, which material comprises a polymer of the formula;

##STR65## wherein R₁ is a member selected from the group of divalent, trivalent and tetravalent radicals consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;

R₂ and R₃ are selected from the group consisting of alkyl of 1 to 7 carbons;

alkenyl of 2 to 7 carbons;

alkoxy of 1 to 7 carbons;

alkenyloxy of 2 to 7 carbons;

alkylene of 2 to 6 carbons;

alkenylene of 3 to 6 carbons;

alkyleneoxy of 2 to 6 carbons;

alkenyleneoxy of 3 to 6 carbons;

aryloxy;

aralkyleneoxy of 8 to 12 carbons;

aralkenyleneoxy of 8 to 12 carbons;

oxa;

OR₁ O with R₁ as defined above;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons; and

wherein at least one of said R.sub. 2 and R₃ is a member selected from the group consisting of alkoxy, alkenyloxy and OR₁ O;

R₂ and R₃ when taken together are a member selected from the group of heterocyclic and fused polycyclic rings having at least one oxygen atom in the ring; and

wherein n is greater than 10;

(d) a drug selected from the group consisting of locally and systemically acting pharmaceutically acceptable drugs present in the cells, said drug dissolved in a pharmaceutically acceptable carrier that is a solvent for the drug and a nonsolvent for the polymer; and

, (e) wherein, when in operation, the device bioerodes at a controlled and continuous rate over a prolonged period of time, thereby administering a therapeutically effective amount of drug in the carrier to the animal at a controlled and continuous rate over a prolonged period of time.

7. A drug delivery device for the controlled and continuous administration of drug, wherein the device comprises:

(a) a matrix shaped, sized and adapted for administering drug to an animal, which matrix is multilayered with the layers formed of a bioerodible drug release rate controlling pharmaceutically acceptable material, said material selected from and comprising a polymer of the formula;

##STR66## wherein R₁ is a member selected from the group of divalent, trivalent, and tetravalent radicals consisting of alkylene of 1 to 10 carbons;

alkenylene of 2 to 10 carbons;

alkyleneoxy of 2 to 6 carbons;

cycloalkylene of 3 to 7 carbons;

cycloalkylene of 3 to 7 carbons substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

cycloalkenylene of 4 to 7 carbons;

cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;

arylene; and

arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons;

R₂ and R₃ are selected from the group consisting of alkyl of 1 to 7 carbons;

alkenyl of 2 to 7 carbons;

alkoxy of 1 to 7 carbons;

alkenyloxy of 2 to 7 carbons;

alkylene of 2 to 6 carbons;

alkenylene of 3 to 6 carbons;

alkyleneoxy of 2 to 6 carbons;

alkenyleneoxy of 3 to 6 carbons;

aryloxy;

aralkyleneoxy of 8 to 12 carbons;

aralkenyleneoxy of 8 to 12 carbons;

oxa;

OR₁ O with R₁ as defined above;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a heterocyclic ring of 5 to 8 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R₂ and R₃ are taken together;

a fused polycyclic ring of 8 to 12 carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons; and

wherein at least one of said R₂ and R₃ is a member selected from the group consisting of alkoxy, alkenyloxy and OR₁ O;

R₂ and R₃ when taken together are a member selected from the group of heterocyclic and fused polycyclic rings having at least one oxygen atom in the ring; and

wherein n is greater than 10;

(b) a plurality of discrete, closed cells in at least one layer;

(c) a drug selected from the group consisting of locally and systemically acting therapeutically acceptable drugs mixed with a pharmaceutically acceptable carrier housed in the cells; and

(d) wherein, when in operation, the device bioerodes at a controlled and continuous rate over a prolonged period of time, thereby administering a therapeutically effective amount of drug mixed with the carrier to the animal at a controlled and continuous rate over a prolonged period of time.