Details for Patent: 5,591,452

Summary for Patent: 5,591,452

Title:	Controlled release formulation
Abstract:	A controlled release preparation for oral administration contains tramadol, or a pharmaceutically acceptable salt thereof, as active ingredient.
Inventor(s):	Ronald B. Miller, Stewart T. Leslie, Sandra T. A. Malkowska, Kevin J. Smith, Walter Wimmer, Horst Winkler, Udo Hahn, Derek A. Prater
Assignee:	NAPP PHARMACEUTICAL GROUP Ltd , Purdue Pharma LP
Application Number:	US08/241,129
Patent Claim Types: see list of patent claims	Composition; Formulation; Dosage form;

United States Patent 5,591,452 (Tramadol Controlled-Release Oral Dosage Forms): Claim Scope and Patent Landscape

United States Patent 5,591,452 claims oral controlled-release (CR) formulations of tramadol (including tramadol salts calculated as hydrochloride) designed for extended dosing intervals (notably once daily and twice daily) and defined by matrix composition plus in vitro release behavior measured by a specific test method (Ph. Eur. Paddle, 0.1N HCl, UV at 270 nm). The claim set uses broad structural ranges (polymer and excipient loading) while tethering operability to tight release-time windows and downstream property targets (tmax and W50).

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What do the claims actually cover? (Core independent claim architecture)

Claim 1: Once-daily CR tramadol with release windows anchored to Ph. Eur. Paddle dissolution

Claim 1 is the broadest chassis and reads as a controlled-release oral pharmaceutical preparation suitable for dosing every 24 hours containing:

• Dose range: about 50 mg to 800 mg tramadol (or pharmaceutically acceptable salt; calculated as hydrochloride).
• Matrix (CR matrix) loading: 1% to 80% w/w of one or more hydrophilic or hydrophobic polymers.
• Dissolution method definition: Ph. Eur. Paddle 100 rpm, 900 mL 0.1N HCl, 37°C, UV detection at 270 nm.
• Release constraints by time (percent released by weight):
  • 1 hour: 0–50%
  • 2 hours: 0–75%
  • 4 hours: 3–95%
  • 8 hours: 10–100%
  • 12 hours: 20–100%
  • 16 hours: 30–100%
  • 24 hours: 50–100%
  • >36 hours: >80%

This is not a simple “controlled release” label. Claim 1 defines CR performance as a set of per-time admissible release ranges, with the most diagnostic anchors at 1, 4, 12, 24, and 36+ hours.

Structural takeaway: Claim 1 is enabled by composition flexibility (polymer(s) total 1–80%), but it is operationally policed by dissolution release windows.

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How do the dependent claims narrow the scope? (Release kinetics tables and excipient ecosystems)

Claims 2–4: Alternate release profile sets (still Ph. Eur. Paddle)

These dependent claims keep the same test framework and specify alternative admissible release tables.

• Claim 2:

  • 1 h: 20–50%
  • 2 h: 40–75%
  • 4 h: 60–95%
  • 8 h: 80–100%
  • 12 h: 90–100%

• Claim 3:

  • 1 h: 0–50%
  • 2 h: 0–75%
  • 4 h: 10–95%
  • 8 h: 35–100%
  • 12 h: 55–100%
  • 16 h: 70–100%
  • 24 h: >90%

• Claim 4:

  • 1 h: 0–30%
  • 2 h: 0–40%
  • 4 h: 3–55%
  • 8 h: 10–65%
  • 12 h: 20–75%
  • 16 h: 30–88%
  • 24 h: 50–100%
  • 36 h: >80%

These dependent claims matter for infringement strategy because they can be read as additional “pick-a-profile” constraints inside the Claim 1 universe.

Claims 5–14: Cellulose ether and specific alkylcellulose + C12–C36 aliphatic alcohol ecosystem

• Claim 5: matrix comprises a cellulose ether.
• Claim 6: controlled release matrix comprises:
  • at least one alkylcellulose
  • at least one C12 to C36 aliphatic alcohol
  • optionally at least one polyalkylglycol
• Claim 7: polyalkylglycol is polyethylene glycol (PEG).
• Claim 8: aliphatic alcohol is C14 to C22.
• Claim 9: alkylcellulose is C1–C6 alkylcellulose.
• Claims 10–14: quantitative and species preferences:
  • alkylcellulose: about 1–20% w/w (Claim 10)
  • aliphatic alcohol species: lauryl, myristyl, stearyl, cetyl, cetostearyl, mixtures (Claim 11)
  • aliphatic alcohol narrower: cetyl alcohol or cetostearyl alcohol (Claim 12)
  • aliphatic alcohol range: 5–30% w/w (Claim 13), preferably 10–25% w/w (Claim 14)

This subgroup is the closest thing to a “formulation recipe claim” inside the set: polymer class + lipid alcohol chain range + PEG option + loading bands.

Claims 15–17: Dosage form architecture (film-coated spheroids, multiparticulates, tableting)

• Claim 15: film-coated spheroids; spheroid matrix has a spheronizing agent.
• Claim 16: multi-particulates with:
  • hydrophobic fusible carrier/diluent melting point 35–140°C
  • optionally a release control component comprising water soluble fusible material or a particulate soluble/insoluble organic or inorganic material
• Claim 17: tablet made by compressing a multiparticulate per Claim 16.

These claims broaden the “how” while staying inside the same controlled release performance envelope (explicitly or by dependency).

Claims 18–19: Specific cellulose ether species (ethylcellulose)

• Claim 18: cellulose ether is alkylcellulose.
• Claim 19: alkylcellulose is ethylcellulose.

This narrows Claim 1/5/6 to a specific alkylcellulose derivative and gives an enforcement target against formulations using ethylcellulose within the matrix.

Claims 20–21: Performance metrics (tmax and W50)

• Claim 20: provides tmax 3–6 hours.
• Claim 21: provides W50 10–33 hours.

These are dissolution-derived or dissolution-correlated measures that can be used to argue functional equivalence even where compositions differ.

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How does the claim set cover twice-daily dosing? (Claim 22 and its dependents)

Claim 22: 12-hour dosing with different release windows

Claim 22 is a second major independent claim direction:

• Dosing interval: every 12 hours
• Dose range: 50–400 mg tramadol (as hydrochloride)
• Matrix polymer loading: 1–80% w/w of hydrophilic or hydrophobic polymers
• Dissolution method: same Ph. Eur. Paddle setup and UV detection (270 nm)
• Release constraints by time:
  • 1 h: 5–50%
  • 2 h: 10–75%
  • 4 h: 20–95%
  • 8 h: 40–100%
  • 12 h: >50%
  • 18 h: >70%
  • 24 h: >80%

Claims 23–34: Cellulose ether and alkylcellulose + aliphatic alcohol + optional PEG

• Claim 23: matrix comprises cellulose ether.
• Claim 24: cellulose ether is alkyl cellulose.
• Claim 25: at least one C1–C6 alkyl cellulose.
• Claim 26: at least one C12–C36 aliphatic alcohol.
• Claim 27: at least one C14–C22 aliphatic alcohol.
• Claim 28: further comprises at least one polyalkylglycol.
• Claim 29: PEG.
• Claims 30–31: alkylcellulose 1–20% w/w (Claim 30), preferably 2–15% w/w (Claim 31).
• Claims 32–34: aliphatic alcohol species set (lauryl, myristyl, stearyl, cetyl, cetostearyl, mixtures) and loading:
  • 5–30% w/w (Claim 33)
  • 10–25% w/w (Claim 34)

Claims 35–39: Multiparticulate spheroids and explicit tmax/W50 targets

• Claim 35: multiparticulate spheroid matrices; spheroid matrix has a spheronizing agent.
• Claim 36: spheronizing agent comprises microcrystalline cellulose.
• Claim 37: multiparticulates with hydrophobic fusible carrier/diluent melting point 35–140°C, and optional fusible release control component or particulate release control component.
• Claim 38: provides tmax 1.5–8 hours.
• Claim 39: provides W50 7–16 hours.

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Claim scope map (what a product must do to land inside the patent)

Infringement “must-haves” for Claim 1

A product is most likely within scope if it has all of the following:

• Oral CR tramadol hydrochloride-equivalent in total daily dosage range (Claim 1: ~50–800 mg).
• Dissolution profile in 0.1N HCl, 900 mL, 100 rpm, 37°C, UV 270 nm meeting the per-time release admissibility bands.
• CR matrix containing 1–80% w/w hydrophilic or hydrophobic polymer(s).
• If enforced via dependent claims: uses cellulose ether (especially alkylcellulose such as ethylcellulose) and possibly includes C12–C36 aliphatic alcohol (preferably C14–C22, e.g., cetyl or cetostearyl) and PEG at the specified ranges.

Infringement “must-haves” for Claim 22

Similar structure, but the gating changes to 12-hour dosing release windows plus tmax/W50 ranges in dependent claims.

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What is the patent landscape likely to look like around this family? (Landscape themes rather than file-by-file mapping)

The claim structure indicates the patent targets three durable, defensible value drivers that show up in later and neighboring CR opioid formulations:

1. Test-method-defined dissolution release windows

   • The claims are not generic. They lock to Ph. Eur. Paddle conditions and UV 270 nm, then set time-sliced release bands (1 h through 36 h for Claim 1; 1 h through 24 h for Claim 22).
   • This is a strong barrier for design-around via “different dissolution result” unless a challenger keeps the same profile behavior.

2. Cellulose ether + aliphatic alcohol + (optional) PEG matrix systems

   • The dependent claims define a polymer-lipid type matrix:
     • alkylcellulose (including ethylcellulose)
     • C12–C36 aliphatic alcohol (narrowed to C14–C22)
     • PEG optional
   • This ecosystem is a common controlled-release mechanism: alcohols and cellulose ethers can tune diffusion and erosion properties, while PEG can modulate microstructure and water penetration.

3. Multiparticulate architecture (spheroids and fusible carriers)

   • Claims cover film-coated spheroids (with spheronizing agent) and multiparticulates using hydrophobic fusible carriers with melting points 35–140°C.
   • This captures common manufacturing platforms for once-daily and twice-daily controlled-release dosage forms (tableting multiparticulates is explicitly claimed).

Business implication: Competitive products that do not meet the specific dissolution release windows may still avoid infringement even if they use similar excipients. Conversely, a product with the right excipient classes but a different release curve may fall outside the claim.

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Design-around pressure points (where competitors will try to move)

Based on claim language, the most likely design-around levers are:

• Shift release timing outside the per-time admissible bands (especially at 1, 4, 12, and 24 hours for Claim 1; and 1, 4, 8, 12, 18, 24 hours for Claim 22).
• Avoid the cellulose ether-aliphatic alcohol-PEG combination if a plaintiff asserts dependent claims (Claims 5–14, 23–34).
• Change the matrix polymer loading or matrix polymer type so it falls outside the 1–80% w/w polymer loading interpretation (though broad, it is still an explicit range).
• Replace the multiparticulate/fusible carrier approach if the dosage-form architecture becomes central (Claims 15–17, 35–37).

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Operational specification checklist (from the claims, verbatim gating inputs)

Any product intended to be compared to this patent should have test and formulation parameters:

Dissolution test

• Apparatus: Ph. Eur. Paddle
• Paddle speed: 100 rpm
• Medium: 900 mL 0.1N HCl
• Temperature: 37°C
• Detection: UV at 270 nm
• Readouts: percent tramadol released at the exact time points used in the claims (1, 2, 4, 8, 12, 16, 24, 36+ for Claim 1; and 1, 2, 4, 8, 12, 18, 24 for Claim 22)

Key compositional bands (if asserting dependent claims)

• Total polymer loading: 1–80% w/w
• Cellulose ether: alkylcellulose preferred
  • alkylcellulose loading: about 1–20% w/w (Claim 10), or 2–15% w/w (Claim 31)
  • ethylcellulose if matching Claims 18–19
• Aliphatic alcohol:
  • chain range: C12–C36 (Claim 6, 26)
  • narrowed: C14–C22 (Claim 8, 27)
  • species: cetyl alcohol / cetostearyl alcohol (Claim 12)
  • loading: 5–30% w/w (Claim 13, 33) or 10–25% w/w (Claim 14, 34)
• PEG optional:
  • polyalkylglycol is polyethylene glycol (Claim 7, 29)

Kinetic metrics (dependent property targets)

• Claim 20: tmax 3–6 hours
• Claim 21: W50 10–33 hours
• Claim 38: tmax 1.5–8 hours
• Claim 39: W50 7–16 hours

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Key Takeaways

• 5,591,452 is engineered around Ph. Eur. Paddle dissolution-defined release bands plus CR matrix composition ranges, not just broad “controlled release” language.
• The independent claim spine splits into once-daily (Claim 1) and twice-daily (Claim 22) regimes, each with distinct time-sliced dissolution constraints.
• The most actionable formulation sub-scope is the alkylcellulose + C12–C36 aliphatic alcohol (+ optional PEG) matrix system, with quantified loading bands and preferred species (including cetyl or cetostearyl alcohol and ethylcellulose).
• Multiparticulate architectures (spheroids and fusible-carrier systems) expand the “how” of construction while leaving the dissolution performance tether intact.

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FAQs

1) Does this patent cover all tramadol ER tablets?

No. Coverage hinges on meeting specific dissolution release windows under the Ph. Eur. Paddle 100 rpm in 0.1N HCl at 37°C with UV 270 nm, plus matrix loading constraints.

2) What are the most diagnostic time points for Claim 1?

Claim 1 constrains release at 1, 4, 12, 24, and 36+ hours through banded ranges, with >80% at >36 hours as a long-tail anchor.

3) What excipient combination is most explicitly claimed?

The dependent claims most strongly emphasize alkylcellulose combined with C12–C36 aliphatic alcohol (narrowed to C14–C22), with PEG optional, and with explicit w/w loading ranges.

4) Can a competitor avoid infringement by using a different cellulosic polymer?

If the patent is enforced via the dependent cellulose-ether claims, avoiding alkylcellulose (including ethylcellulose) would remove a key component of the claimed matrix ecosystem. Independent claim coverage still depends on meeting the dissolution bands and polymer loading range.

5) Are multiparticulate formulations inside scope?

Yes. The claims expressly cover film-coated spheroids and multiparticulates including versions using hydrophobic fusible carriers with melting points 35–140°C, with optional release control components and even compression into tablets.

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References

[1] U.S. Patent No. 5,591,452, “Controlled Release Oral Pharmaceutical Preparation Containing Tramadol,” claim set as provided (Claims 1–39).

Drugs Protected by US Patent 5,591,452

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 5,591,452

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	43 15 525.1	May 10, 1993
United Kingdom	9324045	Nov 23, 1993
United Kingdom	9404544	Mar 09, 1994

International Family Members for US Patent 5,591,452

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	138566
Austria	172376
Austria	184786