Intravaginal drug delivery devices for the administration of 17.beta.-oestradiol precursors
First Claim
1. A cylindrical intravaginal drug delivery device suitable for administration to a female mammal, the device comprising a 17β
- -oestradiol precursor in a biocompatible hydrophobic elastomeric polymer matrix, the device releasing the 17β
-oestradiol precursor in a substantially zero order pattern for at least three weeks, the precursor being a 17β
-oestradiol moiety in which the, or each, hydroxyl group of the 17β
-oestradiol moiety is blocked by a blocking group, the precursor having sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by a standard k value, in which k=2CS Dπ
, of not less than 0.1 μ
g/day/mm, the precursor having sufficient hydrophilicity as determined by a solubility in distilled water of not less than 1 μ
g/100 ml, the, or each, blocking group being so linked to the 17β
-oestradiol moiety as to be readily removed from the 17β
-oestradiol moiety in vivo, and the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal when removed from the 17β
-oestradiol moiety in vivo wherein CS corresponds to the precursor'"'"'s saturation solubility in the polymer matrix and D corresponds to the precursor'"'"'s diffusion coefficient in the polymer matrix.
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Abstract
The invention relates to an intravaginal drug delivery device for administration to a female mammal of certain 17β-oestradiol precursors at a substantially constant rate for a period of at least three weeks. The 17β-oestradiol precursor is a 17β-oestradiol moiety in which the, or each, hydroxyl group of the 17β-oestradiol moiety is blocked by a blocking group, which blocking group is readily removed from the 17β-oestradiol in vivo. The 17β-oestradiol precursor must have either a solubility in liquid silicone of not less than 0.1 mg/100 ml or a standard k value of not less than 0.1 μg/day/mm. The 17β-oestradiol precursor must also have a solubility in distilled water of not less than 1 μg/100 ml.
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Citations
24 Claims
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1. A cylindrical intravaginal drug delivery device suitable for administration to a female mammal, the device comprising a 17β
- -oestradiol precursor in a biocompatible hydrophobic elastomeric polymer matrix, the device releasing the 17β
-oestradiol precursor in a substantially zero order pattern for at least three weeks, the precursor being a 17β
-oestradiol moiety in which the, or each, hydroxyl group of the 17β
-oestradiol moiety is blocked by a blocking group, the precursor having sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by a standard k value, in which k=2CS Dπ
, of not less than 0.1 μ
g/day/mm, the precursor having sufficient hydrophilicity as determined by a solubility in distilled water of not less than 1 μ
g/100 ml, the, or each, blocking group being so linked to the 17β
-oestradiol moiety as to be readily removed from the 17β
-oestradiol moiety in vivo, and the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal when removed from the 17β
-oestradiol moiety in vivo wherein CS corresponds to the precursor'"'"'s saturation solubility in the polymer matrix and D corresponds to the precursor'"'"'s diffusion coefficient in the polymer matrix. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 20, 23, 24)
- -oestradiol precursor in a biocompatible hydrophobic elastomeric polymer matrix, the device releasing the 17β
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15. A process for the preparation of a cylindrical intravaginal drug delivery device for release in a substantially zero order pattern for at least three weeks and suitable for administration to a female mammal, the process comprising the steps of:
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combining a 17β
-oestradiol precursor, the precursor being a 17β
-oestradiol moiety in which the, or each, hydroxyl group of the 17β
-oestradiol moiety is blocked by a blocking group;
the precursor having sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by standard k value as defined hereinabove of not less than 0.1 μ
g/day/mm, the precursor having sufficient hydrophilicity as determined by a solubility in distilled water of not less than 1 μ
g/100 ml, the, or each, blocking group being so linked to the 17β
-oestradiol moiety as to be readily removed from the 17β
-oestradiol moiety in vivo; and
the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal, when removed from the 17β
-oestradiol moiety in vivo, with a biocompatible hydrophobic elastomeric polymer, a suitable cross-linking agent and a curing catalyst to form a mix; andcuring the mix to form a polymer matrix. - View Dependent Claims (16, 17, 21, 22)
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18. A method of using a 17β
- -oestradiol precursor in a cylindrical intravaginal drug delivery device for release in a substantially zero order pattern for at least three weeks, which method comprises the step of incorporating in the drug delivery device the 17β
-oestradiol precursor, wherein the 17β
-oestradiol precursor is a 17β
-oestradiol moiety in which the, or each, hydroxyl group of the 17β
-oestradiol moiety is blocked by a blocking group, the precursor has sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by a standard k value as defined hereinabove of not less than 0.1 μ
g/day/mm, the precursor has sufficient hydrophilicity as determined by a solubility in distilled water of not less than 1 μ
g/100 ml, the, or each, blocking group is so linked to the 17β
-oestradiol moiety as to be readily removed from the 17β
-oestradiol moiety in vivo, and the, or each, blocking group is so chosen as to yield a substance which is non-toxic to the female mammal when removed from the 17β
-oestradiol moiety in vivo.
- -oestradiol precursor in a cylindrical intravaginal drug delivery device for release in a substantially zero order pattern for at least three weeks, which method comprises the step of incorporating in the drug delivery device the 17β
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19. A method of releasing a 17β
- -oestradiol precursor in a substantially zero order pattern for a least three weeks, which method comprises the steps of;
incorporating the 17β
-oestradiol precursor in a cylindrical intravaginal drug delivery device, the 17β
-oestradiol precursor being a 17β
-oestradiol moiety in which the, or each, hydroxyl group of the 17β
-oestradiol moiety is blocked by a blocking group, the precursor having sufficient lipophilicity as determined either by a solubility in liquid silicone of not less than 0.1 mg/100 ml or by a standard k value as defined hereinabove of not less than 0.1 μ
g/100 ml, the precursor having sufficient hydrophilicity, as determined by a solubility in distilled water or not less than 1 μ
g/100 ml, the, or each, blocking group being so linked to the 17β
-oestradiol moiety as to be readily removed from the 17β
-oestradiol moiety in vivo, the, or each, blocking group being so chosen as to yield a substance which is non-toxic to the female mammal when removed from the 17β
-oestradiol moiety in vivo; andinserting the drug delivery device into a vagina of a female mammal for the at least three weeks.
- -oestradiol precursor in a substantially zero order pattern for a least three weeks, which method comprises the steps of;
Specification